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| Ben Affleck | Bartleby/Barry |
| Linda Fiorentino | Bethany Sloane |
| Matt Damon | Loki/Larry |
| George Carlin | Cardinal Ignatius |
| Salma Hayek | Serendipity |
| Jason Lee | Azrael |
| Jason Mewes | Jay |
| Alan Rickman | Metatron |
| Chris Rock | Rufus, the 13th Apostle |
| Bud Cort | John Doe Jersey/God the Man |
| Alanis Morissette | God |
| Kevin Smith | Silent Bob |
| Jeff Anderson | Gun Salesman |
| Brian Christopher O'Halloran | Grant Hicks |
| Janeane Garofalo | Liz |
| Betty Aberlin | Nun |
| Dan Etheridge | St. Stephen's Priest |
| Guinevere Turner | Bus Station Attendant |
| Barrett Hackney | Stygian Triplet |
| Jared Pfennigwerth | Stygian Triplet |
| Kitao Sakurai | Stygian Triplet |
| Benjamin Cain | Gangster #1 |
A female descendant of Jesus must stop two fallen angels who, if successful in getting back into heaven, will destroy the world.
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