diff --git a/changelog.d/20149.bugfix b/changelog.d/20149.bugfix
new file mode 100644
index 0000000000..2440618acf
--- /dev/null
+++ b/changelog.d/20149.bugfix
@@ -0,0 +1 @@
+Fix the `/profile` endpoint, when querying custom fields, returning a 500 error instead of 404 when the profile does not exist at all.
\ No newline at end of file
diff --git a/synapse/storage/databases/main/profile.py b/synapse/storage/databases/main/profile.py
index d5e35fa7ca..fe48636ffb 100644
--- a/synapse/storage/databases/main/profile.py
+++ b/synapse/storage/databases/main/profile.py
@@ -291,11 +291,14 @@ class ProfileWorkerStore(SQLBaseStore):
                     (field_path, field_name, user_id.localpart),
                 )
 
+                row = txn.fetchone()
+                if row is None:
+                    # The user has no profile at all.
+                    raise StoreError(404, "No row found")
+
                 # Test exists first since value being None is used for both
                 # missing and a null JSON value.
-                exists, value = cast(
-                    tuple[bool, JsonValue | dict[str, JsonValue]], txn.fetchone()
-                )
+                exists, value = cast(tuple[bool, JsonValue | dict[str, JsonValue]], row)
                 if not exists:
                     raise StoreError(404, "No row found")
                 return value
@@ -310,9 +313,14 @@ class ProfileWorkerStore(SQLBaseStore):
                     (field_path, field_path, user_id.localpart),
                 )
 
+                row = txn.fetchone()
+                if row is None:
+                    # The user has no profile at all.
+                    raise StoreError(404, "No row found")
+
                 # If value_type is None, then the value did not exist.
                 value_type, value = cast(
-                    tuple[str | None, JsonValue | dict[str, JsonValue]], txn.fetchone()
+                    tuple[str | None, JsonValue | dict[str, JsonValue]], row
                 )
                 if not value_type:
                     raise StoreError(404, "No row found")
diff --git a/tests/storage/test_profile.py b/tests/storage/test_profile.py
index b65af28962..0fc40794c7 100644
--- a/tests/storage/test_profile.py
+++ b/tests/storage/test_profile.py
@@ -19,9 +19,12 @@
 #
 #
 
+from http import HTTPStatus
+
 from twisted.internet.testing import MemoryReactor
 
 from synapse.api.constants import ProfileFields
+from synapse.api.errors import StoreError
 from synapse.server import HomeServer
 from synapse.storage.database import LoggingTransaction
 from synapse.storage.engines import PostgresEngine
@@ -95,6 +98,20 @@ class ProfileStoreTestCase(unittest.HomeserverTestCase):
             self.get_success(self.store.get_profile_avatar_url(self.u_frank))
         )
 
+    def test_get_profile_field_without_profile(self) -> None:
+        """
+        Getting a custom profile field for a user that has no row in the
+        `profiles` table at all should raise a 404.
+
+        Regression test (we previously would trigger an unhandled exception).
+        Can happen for users whose profile was erased upon deactivation.
+        """
+        f = self.get_failure(
+            self.store.get_profile_field(self.u_frank, "org.example.field"),
+            StoreError,
+        )
+        self.assertEqual(f.value.code, HTTPStatus.NOT_FOUND)
+
     def test_profiles_bg_migration(self) -> None:
         """
         Test background job that copies entries from column user_id to full_user_id, adding