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| George Clooney | Everett Ulysses McGill |
| John Turturro | Pete Hogwallop |
| Tim Blake Nelson | Delmar O'Donnel |
| John Goodman | Big Dan Teague |
| Holly Hunter | Penny |
| Chris Thomas King | Tommy Johnson |
| Charles Durning | Governor Pappy O'Daniel |
| Del Pentecost | Junior O'Daniel |
| Michael Badalucco | George "Babyface" Nelson |
| J.R. Horne | Pappy's Staff |
| Brian Reddy | Pappy's Staff |
| Wayne Duvall | Homer Stokes |
| Ed Gale | Little Man |
| Ray McKinnon | Vernon T. Waldrip |
| Daniel Von Bargen | Sheriff Cooley |
| Royce D. Applegate | Man with Bullhorn |
| Frank Collison | Wash Hogwallop |
| Quinn Gasaway | Boy Hogwallop |
| Lee Weaver | Blind Seer |
| Milford Fortenberry | Pomade Vendor |
| Stephen Root | Radio Station Man |
| John Locke | Mr. French |
| Gillian Welch | Soggy Bottom Customer |
| A. Ray Ratliff | Record Store Clerk |
| Mia Tate | Siren |
| Musetta Vander | Siren |
| Christy Taylor | Siren |
| April Hardcastle | Waitress |
| Michael W. Finnell | Interrogator |
| Georgia Rae Rainer | Wharvey Gal |
A mysterious lawman tracks three escaped convicts searching for buried treasure in 1930s Mississippi.
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