diff --git a/Lib/_strptime.py b/Lib/_strptime.py
--- a/Lib/_strptime.py
+++ b/Lib/_strptime.py
@@ -158,26 +158,31 @@ class LocaleTime(object):
         self.LC_date_time = date_time[0]
         self.LC_date = date_time[1]
         self.LC_time = date_time[2]
 
     def __calc_timezone(self):
         # Set self.timezone by using time.tzname.
         # Do not worry about possibility of time.tzname[0] == timetzname[1]
         # and time.daylight; handle that in strptime .
+        (no_saving, has_saving) = self._get_timezone()
+        self.timezone = (no_saving, has_saving)
+
+    @staticmethod
+    def _get_timezone():
         try:
             time.tzset()
         except AttributeError:
             pass
         no_saving = frozenset(["utc", "gmt", time.tzname[0].lower()])
         if time.daylight:
             has_saving = frozenset([time.tzname[1].lower()])
         else:
             has_saving = frozenset()
-        self.timezone = (no_saving, has_saving)
+        return (no_saving, has_saving)
 
 
 class TimeRE(dict):
     """Handle conversion from format directives to regexes."""
 
     def __init__(self, locale_time=None):
         """Create keys/values.
 
@@ -207,25 +212,28 @@ class TimeRE(dict):
             #     4 digits?
             'Y': r"(?P<Y>\d\d\d\d)",
             'z': r"(?P<z>[+-]\d\d[0-5]\d)",
             'A': self.__seqToRE(self.locale_time.f_weekday, 'A'),
             'a': self.__seqToRE(self.locale_time.a_weekday, 'a'),
             'B': self.__seqToRE(self.locale_time.f_month[1:], 'B'),
             'b': self.__seqToRE(self.locale_time.a_month[1:], 'b'),
             'p': self.__seqToRE(self.locale_time.am_pm, 'p'),
-            'Z': self.__seqToRE((tz for tz_names in self.locale_time.timezone
-                                        for tz in tz_names),
-                                'Z'),
+            'Z': self._calculate_timezone(),
             '%': '%'})
         base.__setitem__('W', base.__getitem__('U').replace('U', 'W'))
         base.__setitem__('c', self.pattern(self.locale_time.LC_date_time))
         base.__setitem__('x', self.pattern(self.locale_time.LC_date))
         base.__setitem__('X', self.pattern(self.locale_time.LC_time))
 
+    def _calculate_timezone(self, locale_time=None):
+        if locale_time is None:
+            locale_time = self.locale_time.timezone
+        return self.__seqToRE((tz for tz_names in locale_time for tz in tz_names), 'Z')
+
     def __seqToRE(self, to_convert, directive):
         """Convert a list to a regex string for matching a directive.
 
         Want possible matching values to be from longest to shortest.  This
         prevents the possibility of a match occuring for a value that also
         a substring of a larger value that should have matched (e.g., 'abc'
         matching when 'abcdef' should have been the match).
 
@@ -303,17 +311,21 @@ def _strptime(data_string, format="%a %b
     for index, arg in enumerate([data_string, format]):
         if not isinstance(arg, str):
             msg = "strptime() argument {} must be str, not {}"
             raise TypeError(msg.format(index, type(arg)))
 
     global _TimeRE_cache, _regex_cache
     with _cache_lock:
 
-        if _getlang() != _TimeRE_cache.locale_time.lang:
+        locale_time = _TimeRE_cache.locale_time
+        locale_timezone = locale_time._get_timezone()
+        if locale_time.timezone != locale_timezone:
+            _TimeRE_cache['Z'] = _TimeRE_cache._calculate_timezone(locale_timezone)
+        if _getlang() != locale_time.lang:
             _TimeRE_cache = TimeRE()
             _regex_cache.clear()
         if len(_regex_cache) > _CACHE_MAX_SIZE:
             _regex_cache.clear()
         locale_time = _TimeRE_cache.locale_time
         format_regex = _regex_cache.get(format)
         if not format_regex:
             try:
diff --git a/Lib/test/test_time.py b/Lib/test/test_time.py
--- a/Lib/test/test_time.py
+++ b/Lib/test/test_time.py
@@ -223,16 +223,41 @@ class TimeTestCase(unittest.TestCase):
                 # If mktime fails, ctime will fail too.  This may happen
                 # on some platforms.
                 pass
             else:
                 self.assertEqual(time.ctime(testval)[20:], str(year))
 
     @unittest.skipUnless(hasattr(time, "tzset"),
                          "time module has no attribute tzset")
+    def test_tzset_locale_cache(self):
+        # See issue 6478
+        from os import environ
+
+        try:
+            environ['TZ'] = 'Pacific/Fiji'
+            time.tzset()
+            time.strptime('25-06-2008', '%d-%m-%Y')
+
+            environ['TZ'] = 'America/New_York'
+            time.tzset()
+            time.strptime('Fri Jul 25 13:26:29 EDT 2008',
+                '%a %b %d %H:%M:%S %Z %Y')
+        except ValueError:
+            self.fail('time.tzset does not reset _strptime\'s locale '
+                      'time cache. See issue 6478.')
+        finally:
+            # Repair TZ environment variable in case any other tests
+            # rely on it.
+            if 'TZ' in environ:
+                del environ['TZ']
+            time.tzset()
+
+    @unittest.skipUnless(hasattr(time, "tzset"),
+                         "time module has no attribute tzset")
     def test_tzset(self):
 
         from os import environ
 
         # Epoch time of midnight Dec 25th 2002. Never DST in northern
         # hemisphere.
         xmas2002 = 1040774400.0