diff --git a/pydantic_ai_slim/pydantic_ai/_agent_graph.py b/pydantic_ai_slim/pydantic_ai/_agent_graph.py
index b1a0dd1350..c7c05f4224 100644
--- a/pydantic_ai_slim/pydantic_ai/_agent_graph.py
+++ b/pydantic_ai_slim/pydantic_ai/_agent_graph.py
@@ -216,6 +216,12 @@ async def run(  # noqa: C901
         ctx.state.message_history = messages
         ctx.deps.new_message_index = len(messages)
 
+        # Validate that message history starts with a user message
+        if messages and isinstance(messages[0], _messages.ModelResponse):
+            raise exceptions.UserError(
+                'Message history cannot start with a `ModelResponse`. Conversations must begin with a user message.'
+            )
+
         if self.deferred_tool_results is not None:
             return await self._handle_deferred_tool_results(self.deferred_tool_results, messages, ctx)
 
diff --git a/tests/models/test_outlines.py b/tests/models/test_outlines.py
index 73adc28853..3758e3c404 100644
--- a/tests/models/test_outlines.py
+++ b/tests/models/test_outlines.py
@@ -573,6 +573,7 @@ def test_input_format(transformers_multimodal_model: OutlinesModel, binary_image
 
     # unsupported: tool calls
     tool_call_message_history: list[ModelMessage] = [
+        ModelRequest(parts=[UserPromptPart(content='some user prompt')]),
         ModelResponse(parts=[ToolCallPart(tool_call_id='1', tool_name='get_location')]),
         ModelRequest(parts=[ToolReturnPart(tool_name='get_location', content='London', tool_call_id='1')]),
     ]
@@ -588,7 +589,8 @@ def test_input_format(transformers_multimodal_model: OutlinesModel, binary_image
 
     # unsupported: non-image file parts
     file_part_message_history: list[ModelMessage] = [
-        ModelResponse(parts=[FilePart(content=BinaryContent(data=b'test', media_type='text/plain'))])
+        ModelRequest(parts=[UserPromptPart(content='some user prompt')]),
+        ModelResponse(parts=[FilePart(content=BinaryContent(data=b'test', media_type='text/plain'))]),
     ]
     with pytest.raises(
         UserError, match='File parts other than `BinaryImage` are not supported for Outlines models yet.'
diff --git a/tests/test_agent.py b/tests/test_agent.py
index 29b54643f0..c2a513af47 100644
--- a/tests/test_agent.py
+++ b/tests/test_agent.py
@@ -6132,3 +6132,19 @@ def llm(messages: list[ModelMessage], _info: AgentInfo) -> ModelResponse:
             ]
         )
         assert run.all_messages_json().startswith(b'[{"parts":[{"content":"Hello",')
+
+
+def test_message_history_cannot_start_with_model_response():
+    """Test that message history starting with ModelResponse raises UserError."""
+
+    agent = Agent('test')
+
+    invalid_history = [
+        ModelResponse(parts=[TextPart(content='ai response')]),
+    ]
+
+    with pytest.raises(
+        UserError,
+        match='Message history cannot start with a `ModelResponse`.',
+    ):
+        agent.run_sync('hello', message_history=invalid_history)