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Roddick will play for his 32nd ATP World Tour title on Sunday against Luxembourg's Gilles Muller, who knocked off No. 8 Go Soeda of Japan 6-4, 6-3.
To have a chance to beat his fellow American big server, Roddick had to protect his own serve.
"I did what I was supposed to," Roddick said. "You're not going to beat John if you get broken a lot. I was able to fight off a little bit of trouble early in the first set. I just competed well tonight."
Isner was attempting to win his second straight event for the first time in his seven-year career, but fell short in Atlanta for the third straight year. He lost to Mardy Fish in the past two Atlanta finals.
It's pretty disappointing," Isner said. "(Fish and Roddick are) good friends of mine. It's tough. I've always wanted to win this tournament, but it just wasn't to be. There's really no shame in losing to either of those guys. That's for sure."
Roddick will team up with Isner as U.S. doubles partners when the Olympics begin next week at Wimbledon.
The first set was delayed 44 minutes after Isner took a 3-2 lead. When play resumed, Roddick won four of the next five games and took the set as Isner struggled with his forehand accuracy.
Despite ending the match with 26 aces and winning 81 percent of his first-serve points, Isner was out of sync with his returns. It's a label that's stuck with Isner during his seven-year career.
Isner's lateral footwork looked sluggish, and his forehand kept falling wide or into the net.
"That was pretty apparent to see," Isner said. "I missed a lot of forehands. Then again, in all of my matches this tournament, I missed a lot of forehands. For me to play and do well in the tournament, I need that shot. It wasn't really there for me."
Losing a second-set tiebreaker was tough on Roddick, but he avoided a breaker in the third by breaking Isner in the 10th game of the third set to close out the match.
"(Against) most people in a breaker, you can recover from losing one service point," Roddick said. "Against him, that's not necessarily the case. I'm not sure that I missed a ball besides a service return in the tiebreaker and still lost it. With his serve and weapon he has, a lot of times it's out of your control.
Muller, who will play for his first tour title, had 17 aces to Soeda's two and finished the match in 1 hour, 13 minutes. Muller is 0-2 in career finals and last played for a title in 2005.
"I know if I put a high percentage of my first serve in, I'm getting a lot of free points," Muller said. "I didn't serve that well at the beginning of the week, but yesterday and today was very good."
