Roddick, who will play either No. 5 seed Kevin Anderson or Michael Russell in the quarterfinals, broke Mahut in the ninth game of the tiebreaker and held serve to win the set.
The victory avenged Mahut's four-set victory at the French Open on May 27. It was Roddick's earliest exit from a Grand Slam tournament since 2007 and his first loss to Mahut in five career matches.
No. 1 seed John Isner and No. 2 seed Mardy Fish, Atlanta's two-time defending champion, will play their second-round matches on Thursday.
No. 3 seed Kei Nishikori was to play late Wednesday.

Andy Roddick, of the United States, returns a volley to Nicolas Mahut, of France, during the Atlanta Open tennis tournament on Wednesday night in Atlanta. / photo: Associated Press
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