diff --git a/synapse/handlers/message.py b/synapse/handlers/message.py
index e2c8dc022ced..6cc45f9aaf3a 100644
--- a/synapse/handlers/message.py
+++ b/synapse/handlers/message.py
@@ -1048,6 +1048,13 @@ async def _validate_event_relation(self, event: EventBase) -> None:
             if already_exists:
                 raise SynapseError(400, "Can't send same reaction twice")
 
+        # If this relation is a thread, then ensure thread head is not part of
+        # a thread already.
+        elif relation_type == RelationTypes.THREAD:
+            already_thread = await self.store.get_event_thread(relates_to)
+            if already_thread:
+                raise SynapseError(400, "Can't fork threads")
+
     @measure_func("handle_new_client_event")
     async def handle_new_client_event(
         self,
diff --git a/synapse/storage/databases/main/relations.py b/synapse/storage/databases/main/relations.py
index 40760fbd1b36..bb6e597188aa 100644
--- a/synapse/storage/databases/main/relations.py
+++ b/synapse/storage/databases/main/relations.py
@@ -372,6 +372,37 @@ def _get_if_user_has_annotated_event(txn):
             "get_if_user_has_annotated_event", _get_if_user_has_annotated_event
         )
 
+    async def get_event_thread(self, event_id: str) -> Optional[str]:
+        """Return an event's thread.
+
+        Args:
+            event_id: The event being used as the start of a new thread.
+
+        Returns:
+            The thread ID of the event.
+        """
+
+        sql = """
+            SELECT relates_to_id FROM event_relations
+            WHERE
+                event_id = ?
+                AND relation_type = ?
+            LIMIT 1;
+        """
+
+        def _get_thread_id(txn) -> Optional[str]:
+            txn.execute(
+                sql,
+                (
+                    event_id,
+                    RelationTypes.THREAD,
+                ),
+            )
+
+            return txn.fetchone()
+
+        return await self.db_pool.runInteraction("get_thread_id", _get_thread_id)
+
 
 class RelationsStore(RelationsWorkerStore):
     pass
diff --git a/tests/rest/client/test_relations.py b/tests/rest/client/test_relations.py
index aad7f997ac98..867d4aab24a8 100644
--- a/tests/rest/client/test_relations.py
+++ b/tests/rest/client/test_relations.py
@@ -119,6 +119,25 @@ def test_deny_double_react(self):
         channel = self._send_relation(RelationTypes.ANNOTATION, "m.reaction", "a")
         self.assertEquals(400, channel.code, channel.json_body)
 
+    def test_deny_forked_thread(self):
+        """It is invalid to start a thread off a thread."""
+        channel = self._send_relation(
+            RelationTypes.THREAD,
+            "m.room.message",
+            content={"msgtype": "m.text", "body": "foo"},
+            parent_id=self.parent_id,
+        )
+        self.assertEquals(200, channel.code, channel.json_body)
+        parent_id = channel.json_body["event_id"]
+
+        channel = self._send_relation(
+            RelationTypes.THREAD,
+            "m.room.message",
+            content={"msgtype": "m.text", "body": "foo"},
+            parent_id=parent_id,
+        )
+        self.assertEquals(400, channel.code, channel.json_body)
+
     def test_basic_paginate_relations(self):
         """Tests that calling pagination API correctly the latest relations."""
         channel = self._send_relation(RelationTypes.ANNOTATION, "m.reaction", "a")