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- George Clooney as Ulysses Everett McGill
- Tim Blake Nelson as Delmar O'Donnell
- John Turturro as Pete Hogwallop
- Chris Thomas King as Tommy Johnson
- Frank Collison as Washington B. "Wash" Hogwallop
- John Goodman as Daniel "Big Dan" Teague
- Holly Hunter as Penny McGill
- Charles Durning as Menelaus "Pappy" O'Daniel
- Daniel von Bargen as Sheriff Cooley
- Wayne Duvall as Homer Stokes
- Ray McKinnon as Vernon T. Waldrip
- Michael Badalucco as George Nelson
- Stephen Root as Mr. Lund
- Lee Weaver as The Blind Seer