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Querrey was two points from defeat in the second set tiebreaker but rallied to win it 7-5 and then carried the momentum into the third, breaking his opponent twice to seal his third career title and first of the season.
The American pair, named in the US Davis Cup team to take on Serbia, are friends and frequent practice partners.
"It's tough playing your good buddy like that -- if anyone else could win the tournament, I'd want it to be him, so you're not going to get the same reaction from me about it than if I were playing someone else," Querrey told reporters.
"He'll win some of these and I'll win some of these."
In a battle of big serves from big men, Querrey is 6-foot-6 Querrey and Isner 6-foot-9, neither player was able to break the other in the first two sets.
"I had the match on my racquet," Isner said.
"He played well when it counted though, better than me. It's really hard, because I like to think I've played really well in those situations in the past."
The 22-year-old Querrey's path to the title included a quarter-final upset of defending champion Andy Roddick, who he lost to in the semi-final in San Jose last week.
