Second-seeded American Isner notched his second ATP title in as many weeks afer lifting the trophy in Newport last week.
Atlanta was the perfect place for him to keep the momentum going. Isner, who has reached the final in seven of eight editions of the tournament, added a fourth title to those he won in 2013, 2014 and 2015.
Harrison, seeded fourth, was denied a second career ATP title, to go with his victory in Memphis in February.
Both players held serve throughout the opening set to force the tiebreaker, in which Isner faced a set-point at 5-6 but saved it with a booming serve.
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He then converted a set-point of his own at 7-6 with a forehand winner.
Harrison ended Isner's run of 75 straight service holds -- dating back to last week's Newport tournament -- when he broke for a 2-0 lead in the second set.
But Isner broke back immediately, and they held serve to another tiebreaker.
"We've both got that competitive side where we want to dig in and win," Harrison said. "I think there were times for each of us where things got a little frustrating, but we're really good friends so I really like John as a guy."
His friend Isner responded with an ace, and went on to seal the victory his second match point with a forehand winner up the line.
"It was a battle and took every ounce of my energy out there," Isner said. "Just more importantly, I'm so happy to win this tournament again."
"It feels pretty good for sure," he said. "I've been the top American for the better part of six years now, so to be back in that spot is cool.