diff --git a/doc/source/whatsnew/v0.21.1.txt b/doc/source/whatsnew/v0.21.1.txt
index a9608594be547..73962efad61e7 100644
--- a/doc/source/whatsnew/v0.21.1.txt
+++ b/doc/source/whatsnew/v0.21.1.txt
@@ -56,6 +56,8 @@ Documentation Changes
 
 Bug Fixes
 ~~~~~~~~~
+-
+
 
 Conversion
 ^^^^^^^^^^
@@ -65,6 +67,7 @@ Conversion
 - Bug in :meth:`IntervalIndex.copy` when copying and ``IntervalIndex`` with non-default ``closed`` (:issue:`18339`)
 - Bug in :func:`DataFrame.to_dict` where columns of datetime that are tz-aware were not converted to required arrays when used with ``orient='records'``, raising``TypeError` (:issue:`18372`)
 - Bug in :class:`DateTimeIndex` and :meth:`date_range` where mismatching tz-aware ``start`` and ``end`` timezones would not raise an err if ``end.tzinfo`` is None (:issue:`18431`)
+- Bug in :meth:`Series.fillna` which raised when passed a long integer on Python 2 (:issue:`18159`).
 -
 
 Indexing
diff --git a/pandas/core/internals.py b/pandas/core/internals.py
index e5db5679c43f6..4169a001655cb 100644
--- a/pandas/core/internals.py
+++ b/pandas/core/internals.py
@@ -1847,8 +1847,10 @@ def _can_hold_element(self, element):
         if tipo is not None:
             return (issubclass(tipo.type, (np.floating, np.integer)) and
                     not issubclass(tipo.type, (np.datetime64, np.timedelta64)))
-        return (isinstance(element, (float, int, np.floating, np.int_)) and
-                not isinstance(element, (bool, np.bool_, datetime, timedelta,
+        return (
+            isinstance(
+                element, (float, int, np.floating, np.int_, compat.long))
+            and not isinstance(element, (bool, np.bool_, datetime, timedelta,
                                          np.datetime64, np.timedelta64)))
 
     def to_native_types(self, slicer=None, na_rep='', float_format=None,
@@ -1896,9 +1898,11 @@ def _can_hold_element(self, element):
         if tipo is not None:
             return issubclass(tipo.type,
                               (np.floating, np.integer, np.complexfloating))
-        return (isinstance(element,
-                           (float, int, complex, np.float_, np.int_)) and
-                not isinstance(element, (bool, np.bool_)))
+        return (
+            isinstance(
+                element,
+                (float, int, complex, np.float_, np.int_, compat.long))
+            and not isinstance(element, (bool, np.bool_)))
 
     def should_store(self, value):
         return issubclass(value.dtype.type, np.complexfloating)
diff --git a/pandas/tests/internals/test_internals.py b/pandas/tests/internals/test_internals.py
index a22d0174947e1..08f769e02e267 100644
--- a/pandas/tests/internals/test_internals.py
+++ b/pandas/tests/internals/test_internals.py
@@ -1222,7 +1222,9 @@ class TestCanHoldElement(object):
     @pytest.mark.parametrize('value, dtype', [
         (1, 'i8'),
         (1.0, 'f8'),
+        (2**63, 'f8'),
         (1j, 'complex128'),
+        (2**63, 'complex128'),
         (True, 'bool'),
         (np.timedelta64(20, 'ns'), '<m8[ns]'),
         (np.datetime64(20, 'ns'), '<M8[ns]'),