diff --git a/doc/source/whatsnew/v0.17.0.txt b/doc/source/whatsnew/v0.17.0.txt
index 322f431a37a79..a5bd0dbe95808 100644
--- a/doc/source/whatsnew/v0.17.0.txt
+++ b/doc/source/whatsnew/v0.17.0.txt
@@ -404,4 +404,5 @@ Bug Fixes
 - Bug in ``io.common.get_filepath_or_buffer`` which caused reading of valid S3 files to fail if the bucket also contained keys for which the user does not have read permission (:issue:`10604`)
 - Bug in vectorised setting of timestamp columns with python ``datetime.date`` and numpy ``datetime64`` (:issue:`10408`, :issue:`10412`)
 
+- Bug in ``MultiIndex.__contains__`` throws an ``IndexError`` for large multiindices (:issue:`10645`)
 - Bug in ``pd.DataFrame`` when constructing an empty DataFrame with a string dtype (:issue:`9428`)
diff --git a/pandas/index.pyx b/pandas/index.pyx
index 1678e3b280ee5..9259ed922eb13 100644
--- a/pandas/index.pyx
+++ b/pandas/index.pyx
@@ -143,6 +143,11 @@ cdef class IndexEngine:
                 return self._get_loc_duplicates(val)
             values = self._get_index_values()
             loc = _bin_search(values, val) # .searchsorted(val, side='left')
+
+            # GH10675
+            if len(values) <= loc or 0 > loc:
+                raise KeyError(val)
+
             if util.get_value_at(values, loc) != val:
                 raise KeyError(val)
             return loc
diff --git a/pandas/tests/test_index.py b/pandas/tests/test_index.py
index 81c6366b4cb41..9c0b488a53265 100644
--- a/pandas/tests/test_index.py
+++ b/pandas/tests/test_index.py
@@ -1253,6 +1253,14 @@ def test_get_loc(self):
         with tm.assertRaises(TypeError):
             idx.get_loc('a', method='nearest')
 
+    def test_get_loc_keyerror(self):
+        # GH10645
+        mi = pd.MultiIndex.from_arrays([range(100), range(100)])
+        self.assertRaises(KeyError, lambda: mi.get_loc((1000001, 0)))
+
+        mi = pd.MultiIndex.from_arrays([range(1000000), range(1000000)])
+        self.assertRaises(KeyError, lambda: mi.get_loc((1000001, 0)))
+
     def test_slice_locs(self):
         for dtype in [int, float]:
             idx = Index(np.array([0, 1, 2, 5, 6, 7, 9, 10], dtype=dtype))