diff --git a/changelog.d/15163.bugfix b/changelog.d/15163.bugfix
new file mode 100644
index 000000000..7ff1cd446
--- /dev/null
+++ b/changelog.d/15163.bugfix
@@ -0,0 +1 @@
+Fix a long-standing bug where an initial sync would not respond to changes to the list of ignored users if there was an initial sync cached.
\ No newline at end of file
diff --git a/synapse/rest/client/sync.py b/synapse/rest/client/sync.py
index f2013faeb..8fcb8ac3d 100644
--- a/synapse/rest/client/sync.py
+++ b/synapse/rest/client/sync.py
@@ -16,7 +16,7 @@ import logging
 from collections import defaultdict
 from typing import TYPE_CHECKING, Any, Dict, List, Optional, Tuple, Union
 
-from synapse.api.constants import EduTypes, Membership, PresenceState
+from synapse.api.constants import AccountDataTypes, EduTypes, Membership, PresenceState
 from synapse.api.errors import Codes, StoreError, SynapseError
 from synapse.api.filtering import FilterCollection
 from synapse.api.presence import UserPresenceState
@@ -139,7 +139,28 @@ class SyncRestServlet(RestServlet):
             device_id,
         )
 
-        request_key = (user, timeout, since, filter_id, full_state, device_id)
+        # Stream position of the last ignored users account data event for this user,
+        # if we're initial syncing.
+        # We include this in the request key to invalidate an initial sync
+        # in the response cache once the set of ignored users has changed.
+        # (We filter out ignored users from timeline events, so our sync response
+        # is invalid once the set of ignored users changes.)
+        last_ignore_accdata_streampos: Optional[int] = None
+        if not since:
+            # No `since`, so this is an initial sync.
+            last_ignore_accdata_streampos = await self.store.get_latest_stream_id_for_global_account_data_by_type_for_user(
+                user.to_string(), AccountDataTypes.IGNORED_USER_LIST
+            )
+
+        request_key = (
+            user,
+            timeout,
+            since,
+            filter_id,
+            full_state,
+            device_id,
+            last_ignore_accdata_streampos,
+        )
 
         if filter_id is None:
             filter_collection = self.filtering.DEFAULT_FILTER_COLLECTION
diff --git a/synapse/storage/databases/main/account_data.py b/synapse/storage/databases/main/account_data.py
index 95567826f..308d19440 100644
--- a/synapse/storage/databases/main/account_data.py
+++ b/synapse/storage/databases/main/account_data.py
@@ -237,6 +237,37 @@ class AccountDataWorkerStore(PushRulesWorkerStore, CacheInvalidationWorkerStore)
         else:
             return None
 
+    async def get_latest_stream_id_for_global_account_data_by_type_for_user(
+        self, user_id: str, data_type: str
+    ) -> Optional[int]:
+        """
+        Returns:
+            The stream ID of the account data,
+            or None if there is no such account data.
+        """
+
+        def get_latest_stream_id_for_global_account_data_by_type_for_user_txn(
+            txn: LoggingTransaction,
+        ) -> Optional[int]:
+            sql = """
+                SELECT stream_id FROM account_data
+                WHERE user_id = ? AND account_data_type = ?
+                ORDER BY stream_id DESC
+                LIMIT 1
+            """
+            txn.execute(sql, (user_id, data_type))
+
+            row = txn.fetchone()
+            if row:
+                return row[0]
+            else:
+                return None
+
+        return await self.db_pool.runInteraction(
+            "get_latest_stream_id_for_global_account_data_by_type_for_user",
+            get_latest_stream_id_for_global_account_data_by_type_for_user_txn,
+        )
+
     @cached(num_args=2, tree=True)
     async def get_account_data_for_room(
         self, user_id: str, room_id: str
diff --git a/tests/storage/test_account_data.py b/tests/storage/test_account_data.py
index 1bfd11cea..b12691a9d 100644
--- a/tests/storage/test_account_data.py
+++ b/tests/storage/test_account_data.py
@@ -140,3 +140,25 @@ class IgnoredUsersTestCase(unittest.HomeserverTestCase):
         # No one ignores the user now.
         self.assert_ignored(self.user, set())
         self.assert_ignorers("@other:test", set())
+
+    def test_ignoring_users_with_latest_stream_ids(self) -> None:
+        """Test that ignoring users updates the latest stream ID for the ignored
+        user list account data."""
+
+        def get_latest_ignore_streampos(user_id: str) -> Optional[int]:
+            return self.get_success(
+                self.store.get_latest_stream_id_for_global_account_data_by_type_for_user(
+                    user_id, AccountDataTypes.IGNORED_USER_LIST
+                )
+            )
+
+        self.assertIsNone(get_latest_ignore_streampos("@user:test"))
+
+        self._update_ignore_list("@other:test", "@another:remote")
+
+        self.assertEqual(get_latest_ignore_streampos("@user:test"), 2)
+
+        # Add one user, remove one user, and leave one user.
+        self._update_ignore_list("@foo:test", "@another:remote")
+
+        self.assertEqual(get_latest_ignore_streampos("@user:test"), 3)