diff --git a/newsfragments/2185.bugfix.rst b/newsfragments/2185.bugfix.rst
new file mode 100644
index 0000000000..cb4f8c097f
--- /dev/null
+++ b/newsfragments/2185.bugfix.rst
@@ -0,0 +1 @@
+Fix bug in _is_latest_block_number_request in cache middleware
diff --git a/tests/core/middleware/test_latest_block_based_cache_middleware.py b/tests/core/middleware/test_latest_block_based_cache_middleware.py
index 2c5b529174..104a986062 100644
--- a/tests/core/middleware/test_latest_block_based_cache_middleware.py
+++ b/tests/core/middleware/test_latest_block_based_cache_middleware.py
@@ -250,3 +250,28 @@ def error_cb(method, params):
         w3.manager.request_blocking('fake_endpoint', [])
 
     assert next(counter) == 2
+
+
+def test_latest_block_cache_middleware_does_not_cache_get_latest_block(
+        w3_base,
+        block_data_middleware,
+        result_generator_middleware):
+    w3 = w3_base
+    w3.middleware_onion.add(block_data_middleware)
+    w3.middleware_onion.add(result_generator_middleware)
+
+    current_block_hash = w3.eth.get_block('latest')['hash']
+
+    def cache_class():
+        return {
+            generate_cache_key(
+                (current_block_hash, 'eth_getBlockByNumber', ['latest'])
+            ): {'result': 'value-a'},
+        }
+
+    w3.middleware_onion.add(construct_latest_block_based_cache_middleware(
+        cache_class=cache_class,
+        rpc_whitelist={'eth_getBlockByNumber'},
+    ))
+
+    assert w3.manager.request_blocking('eth_getBlockByNumber', ['latest']) != 'value-a'
diff --git a/web3/middleware/cache.py b/web3/middleware/cache.py
index 91331327bc..953aa4cdfe 100644
--- a/web3/middleware/cache.py
+++ b/web3/middleware/cache.py
@@ -12,6 +12,9 @@
     cast,
 )
 
+from eth_utils import (
+    is_list_like,
+)
 import lru
 
 from web3._utils.caching import (
@@ -318,7 +321,7 @@ def middleware(method: RPCEndpoint, params: Any) -> RPCResponse:
 def _is_latest_block_number_request(method: RPCEndpoint, params: Any) -> bool:
     if method != 'eth_getBlockByNumber':
         return False
-    elif params[:1] == ['latest']:
+    elif is_list_like(params) and tuple(params[:1]) == ('latest',):
         return True
     return False