diff --git a/changes/4040.feature.md b/changes/4040.feature.md
new file mode 100644
index 0000000000..7e2813ed5d
--- /dev/null
+++ b/changes/4040.feature.md
@@ -0,0 +1 @@
+`zarr.experimental.cache_store.CacheStore` now performs negative caching by default (`cache_missing=True`, opt-out). A full-key read that finds the key absent in the source store is remembered, so repeat reads of that absent key return immediately without a source round-trip — useful for sparse arrays where most chunks resolve to the fill value. Remembered misses respect `max_age_seconds` and are evicted when the key is written via `set`/`set_if_not_exists`. Negative-cache activity is reported as `negative_hits` in `cache_stats()` and `missing_keys` in `cache_info()`. Only full-key reads are affected (not byte-range reads or `exists`). Pass `cache_missing=False` to restore the previous behavior. Like the positive cache (unbounded when `max_size is None`), the negative cache is bounded only by `max_age_seconds`; set a finite TTL for scans over very large sparse key spaces.
diff --git a/src/zarr/experimental/cache_store.py b/src/zarr/experimental/cache_store.py
index 1535b42f67..4205686fb6 100644
--- a/src/zarr/experimental/cache_store.py
+++ b/src/zarr/experimental/cache_store.py
@@ -30,8 +30,14 @@ class _CacheState:
     hits: int = 0
     misses: int = 0
     evictions: int = 0
+    negative_hits: int = 0
     key_insert_times: dict[_CacheEntryKey, float] = field(default_factory=dict)
     range_cache: dict[str, dict[ByteRequest, Buffer]] = field(default_factory=dict)
+    # Negative cache: full keys known to be absent in the source store, mapped to their
+    # (monotonic) insertion time. Used to short-circuit repeat reads of absent keys.
+    # Entries carry no data, so they are kept out of the byte-size accounting above;
+    # staleness is bounded by ``max_age_seconds``.
+    missing_keys: dict[str, float] = field(default_factory=dict)
 
 
 class CacheStore(WrapperStore[Store]):
@@ -62,6 +68,26 @@ class CacheStore(WrapperStore[Store]):
         Note: Individual values larger than max_size will not be cached.
     cache_set_data : bool, optional
         Whether to cache data when it's written to the store. Default is True.
+    cache_missing : bool, optional
+        Whether to remember full-key misses (negative caching). When True, a full-key
+        ``get`` that finds the key absent in the source store records that absence, so
+        subsequent ``get``s for the same key return ``None`` without a source round-trip.
+        This benefits repeated reads of sparse arrays (most chunks absent). Negative
+        entries respect ``max_age_seconds`` and are evicted when the key is written
+        (``set``/``set_if_not_exists``). Only full-key reads are affected (not byte-range
+        reads or ``exists``). Default is True.
+
+        Notes:
+
+        - With ``max_age_seconds="infinity"`` (the default) a remembered miss never
+          expires, so a key written to the source by another process stays invisible
+          through this cache. Pair ``cache_missing=True`` with a finite
+          ``max_age_seconds`` if the source may be written concurrently.
+        - Like the positive cache (which is unbounded when ``max_size is None``), the
+          negative cache is bounded only by ``max_age_seconds``. With an infinite TTL,
+          a scan over a very large sparse key space will accumulate one small entry per
+          absent key. Set a finite ``max_age_seconds`` (or ``cache_missing=False``) for
+          such workloads.
 
     Examples
     --------
@@ -91,6 +117,7 @@ class CacheStore(WrapperStore[Store]):
     max_age_seconds: int | Literal["infinity"]
     max_size: int | None
     cache_set_data: bool
+    cache_missing: bool
     _state: _CacheState
 
     def __init__(
@@ -101,6 +128,7 @@ def __init__(
         max_age_seconds: int | str = "infinity",
         max_size: int | None = None,
         cache_set_data: bool = True,
+        cache_missing: bool = True,
     ) -> None:
         super().__init__(store)
 
@@ -121,6 +149,7 @@ def __init__(
             self.max_age_seconds = max_age_seconds
         self.max_size = max_size
         self.cache_set_data = cache_set_data
+        self.cache_missing = cache_missing
         self._state = _CacheState()
 
     def _with_store(self, store: Store) -> Self:
@@ -136,6 +165,7 @@ def with_read_only(self, read_only: bool = False) -> Self:
             max_age_seconds=self.max_age_seconds,
             max_size=self.max_size,
             cache_set_data=self.cache_set_data,
+            cache_missing=self.cache_missing,
         )
         store._state = self._state
         return store
@@ -151,6 +181,31 @@ def _is_key_fresh(self, entry_key: _CacheEntryKey) -> bool:
         elapsed = now - self._state.key_insert_times.get(entry_key, 0)
         return elapsed < self.max_age_seconds
 
+    def _is_missing_fresh(self, key: str) -> bool:
+        """Check if a negative (missing-key) entry is still fresh.
+
+        Mirrors ``_is_key_fresh`` but reads the negative-cache insertion time.
+        """
+        if self.max_age_seconds == "infinity":
+            return True
+        elapsed = time.monotonic() - self._state.missing_keys.get(key, 0.0)
+        return elapsed < self.max_age_seconds
+
+    def _record_missing(self, key: str) -> None:
+        """Record *key* as known-missing (absent in the source store).
+
+        Must be called while holding ``self._state.lock``. Staleness is bounded by
+        ``max_age_seconds`` via ``_is_missing_fresh``.
+        """
+        self._state.missing_keys[key] = time.monotonic()
+
+    def _evict_missing(self, key: str) -> None:
+        """Drop any negative entry for *key* (it is now present or being written).
+
+        Must be called while holding ``self._state.lock``.
+        """
+        self._state.missing_keys.pop(key, None)
+
     async def _accommodate_value(self, value_size: int) -> None:
         """Ensure there is enough space in the cache for a new value.
 
@@ -266,6 +321,10 @@ async def _cache_miss(
                 await self._cache.delete(key)
                 async with self._state.lock:
                     self._remove_from_tracking(key)
+                    # The key is absent in the source: remember the miss so a repeat
+                    # read can short-circuit without a source round-trip.
+                    if self.cache_missing:
+                        self._record_missing(key)
             else:
                 entry_key: _CacheEntryKey = (key, byte_range)
                 async with self._state.lock:
@@ -279,6 +338,10 @@ async def _cache_miss(
             if byte_range is None:
                 await self._cache.set(key, result)
                 await self._track_entry(key, result)
+                # A value now exists for this key: drop any stale negative entry.
+                if self.cache_missing:
+                    async with self._state.lock:
+                        self._evict_missing(key)
             else:
                 entry_key = (key, byte_range)
                 self._state.range_cache.setdefault(key, {})[byte_range] = result
@@ -351,6 +414,16 @@ async def get(
         Buffer | None
             The retrieved data, or None if not found
         """
+        # Negative cache fast-path (full-key reads only): a fresh "known absent" record
+        # short-circuits to None without consulting the positive cache or the source.
+        # Checked here, before the positive-entry freshness gate, because a negative-only
+        # key has no positive entry and would otherwise be routed straight to the source.
+        if self.cache_missing and byte_range is None:
+            async with self._state.lock:
+                if key in self._state.missing_keys and self._is_missing_fresh(key):
+                    self._state.negative_hits += 1
+                    return None
+
         entry_key: _CacheEntryKey = (key, byte_range) if byte_range is not None else key
         if not self._is_key_fresh(entry_key):
             return await self._get_no_cache(key, prototype, byte_range)
@@ -369,9 +442,12 @@ async def set(self, key: str, value: Buffer) -> None:
             The data to store
         """
         await super().set(key, value)
-        # Invalidate all cached byte-range entries (source data changed)
+        # Invalidate all cached byte-range entries (source data changed) and drop any
+        # negative entry — the key now has a value.
         async with self._state.lock:
             self._invalidate_range_entries(key)
+            if self.cache_missing:
+                self._evict_missing(key)
         if self.cache_set_data:
             await self._cache.set(key, value)
             await self._track_entry(key, value)
@@ -380,6 +456,26 @@ async def set(self, key: str, value: Buffer) -> None:
             async with self._state.lock:
                 self._remove_from_tracking(key)
 
+    async def set_if_not_exists(self, key: str, value: Buffer) -> None:
+        """
+        Store data only if the key does not already exist in the source store.
+
+        Parameters
+        ----------
+        key : str
+            The key to store under
+        value : Buffer
+            The data to store
+        """
+        await super().set_if_not_exists(key, value)
+        # Whether or not the write happened, any negative entry is now unsafe: either
+        # we just wrote the key, or it already existed (so the record was already
+        # wrong). Evicting unconditionally is always safe. We do not populate the
+        # positive cache here — there is no guaranteed-fresh value to store.
+        if self.cache_missing:
+            async with self._state.lock:
+                self._evict_missing(key)
+
     async def delete(self, key: str) -> None:
         """
         Delete data from both the underlying store and cache.
@@ -407,18 +503,26 @@ def cache_info(self) -> dict[str, Any]:
             "max_size": self.max_size,
             "current_size": self._state.current_size,
             "cache_set_data": self.cache_set_data,
+            "cache_missing": self.cache_missing,
             "tracked_keys": len(self._state.key_insert_times),
             "cached_keys": len(self._state.cache_order),
+            "missing_keys": len(self._state.missing_keys),
         }
 
     def cache_stats(self) -> dict[str, Any]:
-        """Return cache performance statistics."""
+        """Return cache performance statistics.
+
+        ``hit_rate`` reflects positive-cache hits over positive lookups only; a
+        negative-cache hit (an absent key served from the negative cache) is reported
+        separately as ``negative_hits`` and is counted as neither a hit nor a miss.
+        """
         total_requests = self._state.hits + self._state.misses
         hit_rate = self._state.hits / total_requests if total_requests > 0 else 0.0
         return {
             "hits": self._state.hits,
             "misses": self._state.misses,
             "evictions": self._state.evictions,
+            "negative_hits": self._state.negative_hits,
             "total_requests": total_requests,
             "hit_rate": hit_rate,
         }
@@ -435,7 +539,9 @@ async def clear_cache(self) -> None:
             self._state.cache_order.clear()
             self._state.key_sizes.clear()
             self._state.range_cache.clear()
+            self._state.missing_keys.clear()
             self._state.current_size = 0
+            self._state.negative_hits = 0
 
     def __repr__(self) -> str:
         """Return string representation of the cache store."""
diff --git a/tests/test_experimental/test_cache_store.py b/tests/test_experimental/test_cache_store.py
index fc17ccd5e1..17ee32c5c4 100644
--- a/tests/test_experimental/test_cache_store.py
+++ b/tests/test_experimental/test_cache_store.py
@@ -298,8 +298,10 @@ async def test_cache_info(self, cached_store: CacheStore) -> None:
             "max_size",
             "current_size",
             "cache_set_data",
+            "cache_missing",
             "tracked_keys",
             "cached_keys",
+            "missing_keys",
         }
         assert set(info.keys()) == expected_keys
 
@@ -1047,3 +1049,131 @@ async def test_delete_invalidates_cached_byte_ranges(self) -> None:
         # Key is gone from source
         result = await cached_store.get("key", proto)
         assert result is None
+
+
+class TestCacheStoreNegativeCaching:
+    """Tests for opt-in negative (missing-key) caching (``cache_missing=True``)."""
+
+    async def test_basic(self, monkeypatch: pytest.MonkeyPatch) -> None:
+        """A second get of an absent key is served from the negative cache without a
+        source round-trip."""
+        source = MemoryStore()
+        cs = CacheStore(source, cache_store=MemoryStore(), cache_missing=True)
+        proto = default_buffer_prototype()
+
+        calls = {"n": 0}
+        orig_get = source.get
+
+        async def counting_get(*args: object, **kwargs: object) -> object:
+            calls["n"] += 1
+            return await orig_get(*args, **kwargs)  # type: ignore[arg-type]
+
+        monkeypatch.setattr(source, "get", counting_get)
+
+        assert await cs.get("c/0", proto) is None
+        assert cs.cache_info()["missing_keys"] == 1
+        after_first = calls["n"]
+
+        assert await cs.get("c/0", proto) is None
+        assert calls["n"] == after_first  # no further source access
+        assert cs.cache_stats()["negative_hits"] == 1
+
+    async def test_enabled_by_default(self) -> None:
+        """Negative caching is on by default (opt-out)."""
+        cs = CacheStore(MemoryStore(), cache_store=MemoryStore())
+        proto = default_buffer_prototype()
+        assert cs.cache_missing is True
+        assert await cs.get("c/0", proto) is None
+        assert await cs.get("c/0", proto) is None
+        assert cs.cache_info()["missing_keys"] == 1
+        assert cs.cache_stats()["negative_hits"] == 1
+
+    async def test_can_be_disabled(self) -> None:
+        """With ``cache_missing=False`` nothing is remembered."""
+        cs = CacheStore(MemoryStore(), cache_store=MemoryStore(), cache_missing=False)
+        proto = default_buffer_prototype()
+        assert await cs.get("c/0", proto) is None
+        assert await cs.get("c/0", proto) is None
+        assert cs.cache_info()["missing_keys"] == 0
+        assert cs.cache_stats()["negative_hits"] == 0
+
+    async def test_evicted_on_set(self) -> None:
+        source = MemoryStore()
+        cs = CacheStore(source, cache_store=MemoryStore(), cache_missing=True)
+        proto = default_buffer_prototype()
+        assert await cs.get("c/0", proto) is None
+        assert cs.cache_info()["missing_keys"] == 1
+
+        await cs.set("c/0", CPUBuffer.from_bytes(b"value"))
+        assert cs.cache_info()["missing_keys"] == 0
+        result = await cs.get("c/0", proto)
+        assert result is not None
+        assert result.to_bytes() == b"value"
+
+    async def test_evicted_on_set_if_not_exists(self) -> None:
+        source = MemoryStore()
+        cs = CacheStore(source, cache_store=MemoryStore(), cache_missing=True)
+        proto = default_buffer_prototype()
+        assert await cs.get("c/0", proto) is None
+        assert cs.cache_info()["missing_keys"] == 1
+
+        await cs.set_if_not_exists("c/0", CPUBuffer.from_bytes(b"value"))
+        assert cs.cache_info()["missing_keys"] == 0
+        result = await cs.get("c/0", proto)
+        assert result is not None
+        assert result.to_bytes() == b"value"
+
+    async def test_respects_ttl(self) -> None:
+        """A negative entry expires after ``max_age_seconds`` so a key written to the
+        source out-of-band becomes visible again."""
+        source = MemoryStore()
+        cs = CacheStore(source, cache_store=MemoryStore(), cache_missing=True, max_age_seconds=1)
+        proto = default_buffer_prototype()
+        assert await cs.get("c/0", proto) is None
+
+        # an external writer adds the key directly to the source store
+        await source.set("c/0", CPUBuffer.from_bytes(b"late"))
+
+        # before TTL: still reported missing from the negative cache
+        assert await cs.get("c/0", proto) is None
+        await asyncio.sleep(1.1)
+
+        # after TTL: the stale negative entry is bypassed, source is consulted
+        result = await cs.get("c/0", proto)
+        assert result is not None
+        assert result.to_bytes() == b"late"
+        assert cs.cache_info()["missing_keys"] == 0
+
+    async def test_byte_range_unaffected(self) -> None:
+        """Byte-range misses do not populate the negative cache."""
+        cs = CacheStore(MemoryStore(), cache_store=MemoryStore(), cache_missing=True)
+        proto = default_buffer_prototype()
+        assert await cs.get("c/0", proto, byte_range=RangeByteRequest(0, 4)) is None
+        assert cs.cache_info()["missing_keys"] == 0
+
+    async def test_stats_and_info(self) -> None:
+        """``negative_hits``/``missing_keys``/``cache_missing`` are surfaced and the
+        positive ``hit_rate`` is unaffected by negative hits."""
+        source = MemoryStore()
+        cs = CacheStore(source, cache_store=MemoryStore(), cache_missing=True)
+        proto = default_buffer_prototype()
+
+        await cs.set("present", CPUBuffer.from_bytes(b"x"))
+        assert (await cs.get("present", proto)) is not None  # positive hit
+        assert await cs.get("absent", proto) is None  # records miss
+        assert await cs.get("absent", proto) is None  # negative hit
+
+        info = cs.cache_info()
+        stats = cs.cache_stats()
+        assert info["cache_missing"] is True
+        assert info["missing_keys"] == 1
+        assert stats["negative_hits"] == 1
+        assert stats["hits"] == 1
+        assert stats["misses"] == 1  # negative hit counts as neither hit nor miss
+        assert stats["hit_rate"] == 0.5
+
+    async def test_delete_does_not_record(self) -> None:
+        """Deleting a key does not create a negative entry (deletion != checked-absent)."""
+        cs = CacheStore(MemoryStore(), cache_store=MemoryStore(), cache_missing=True)
+        await cs.delete("c/0")
+        assert cs.cache_info()["missing_keys"] == 0