In the tiebreaker, the Bryan brothers rallied from 4-2 down to clinch the victory when Mahut sent a forehand wide. The Bryans won their only other French Open in 2003. They lost in the final in 2005, 2006 and 2012.
When they won the Australian Open this year, they broke a tie for most doubles majors with Australian greats John Newcombe and Tony Roche.
Llodra and Mahut were bidding to become the first Frenchmen to win the doubles since Yannick Noah and Henri Leconte in 1984.
In the first set, the Bryans put pressure on Llodra's serve in the opening game, forcing their opponents to save five break points.
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The Americans broke for 3-2 when Mahut hit a forehand volley long. They took the first set on Llodra's backhand return that sailed long.
The French fought back in the second set, relying on their powerful serve. They combined for 15 aces in the match compared to only three for the Bryans.
The Bryans broke back in the next game as Mike hit a backhand return winner. Then in a heated rally at 3-3, Mike fired a smash into Mahut's left calf.
Mike apologised but the crowd still booed him as Mahut wobbled for a few seconds. Mahut had his leg treated with a spray during the changeover at 5-4 and then at 2-1 in the third.
The French pair evened the match by taking Bob's serve as Llodra converted his first set point with a backhand pass down the middle.