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Mekhi ficou mais conhecido pelo seu papel em ER como o Dr. Greg Pratt por 7 temporadas (2001-2008). Nascido e criado no Harlem (Nova York), Mekhi foi originalmente contratado com um rapper pela Warner. Atuou também em filmes como 8 Mile, com Eminem, Dawn of the Dead, Shaft , Ouro Branco, Honey e fez particação especial no seriado Curb Your Enthusiasm.
Tem dois filhos: um com a atriz Malinda Williams (Omikaye) e outro com a atual noiva Oni Souratha (Mekhi Thira Phifer, Jr.).
Atualmente, atua na série "Lie to Me", transmitida pelo canal pago FOX.
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