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| Wesley Snipes | Blade |
| Kris Kristofferson | Abraham Whistler |
| Jessica Biel | Abigail Whistler |
| Ryan Reynolds | Hannibal King |
| Parker Posey | Danica |
| Dominic Purcell | Dracula/Drake |
| John Michael Higgins | Dr. Edgar Vance |
| James Remar | Ray Cumberland |
| Eric Bogosian | Bentley Tittle |
| Patton Oswalt | Hedges |
| Callum Keith Rennie | Asher |
| Natasha Lyonne | Sommerfield |
| Mark Berry | Chief Martin Vreede |
| Steve Braun | FBI Agent Wilson Hale |
| Hunter Hearst Helmsley | Jarko Grimwood |
Blade and a pair of vampire slayers battle Dracula, the newly resurrected ancestor of the undead.
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