diff --git a/doc/source/whatsnew/v0.23.0.txt b/doc/source/whatsnew/v0.23.0.txt
index af1bee435eead..940505c01d6c6 100644
--- a/doc/source/whatsnew/v0.23.0.txt
+++ b/doc/source/whatsnew/v0.23.0.txt
@@ -1254,6 +1254,7 @@ Indexing
 - Bug in ``.loc`` assignment with a single-element list-like incorrectly assigns as a list (:issue:`19474`)
 - Bug in partial string indexing on a ``Series/DataFrame`` with a monotonic decreasing ``DatetimeIndex`` (:issue:`19362`)
 - Bug in :meth:`IntervalIndex.get_loc` and :meth:`IntervalIndex.get_indexer` when used with an :class:`IntervalIndex` containing a single interval (:issue:`17284`, :issue:`20921`)
+- Bug in ``.loc`` with a ``uint64`` indexer (:issue:`20722`)
 
 MultiIndex
 ^^^^^^^^^^
diff --git a/pandas/_libs/khash.pxd b/pandas/_libs/khash.pxd
index b1d965c3618cd..4c00e273b33b7 100644
--- a/pandas/_libs/khash.pxd
+++ b/pandas/_libs/khash.pxd
@@ -84,9 +84,9 @@ cdef extern from "khash_python.h":
     kh_uint64_t* kh_init_uint64() nogil
     void kh_destroy_uint64(kh_uint64_t*) nogil
     void kh_clear_uint64(kh_uint64_t*) nogil
-    khint_t kh_get_uint64(kh_uint64_t*, int64_t) nogil
+    khint_t kh_get_uint64(kh_uint64_t*, uint64_t) nogil
     void kh_resize_uint64(kh_uint64_t*, khint_t) nogil
-    khint_t kh_put_uint64(kh_uint64_t*, int64_t, int*) nogil
+    khint_t kh_put_uint64(kh_uint64_t*, uint64_t, int*) nogil
     void kh_del_uint64(kh_uint64_t*, khint_t) nogil
 
     bint kh_exist_uint64(kh_uint64_t*, khiter_t) nogil
diff --git a/pandas/tests/indexing/test_loc.py b/pandas/tests/indexing/test_loc.py
index 6ccff7e898a6a..2e52154d7679b 100644
--- a/pandas/tests/indexing/test_loc.py
+++ b/pandas/tests/indexing/test_loc.py
@@ -784,3 +784,22 @@ def convert_nested_indexer(indexer_type, keys):
             index=pd.MultiIndex.from_product(keys))
 
         tm.assert_series_equal(result, expected)
+
+    def test_loc_uint64(self):
+        # GH20722
+        # Test whether loc accept uint64 max value as index.
+        s = pd.Series([1, 2],
+                      index=[np.iinfo('uint64').max - 1,
+                             np.iinfo('uint64').max])
+
+        result = s.loc[np.iinfo('uint64').max - 1]
+        expected = s.iloc[0]
+        assert result == expected
+
+        result = s.loc[[np.iinfo('uint64').max - 1]]
+        expected = s.iloc[[0]]
+        tm.assert_series_equal(result, expected)
+
+        result = s.loc[[np.iinfo('uint64').max - 1,
+                       np.iinfo('uint64').max]]
+        tm.assert_series_equal(result, s)