American Reilly Opelka upset John Isner with a 7-6 (7/2) 6-7 (5/7) 7-6 (7/5) victory in the second round of the Atlanta Open here.
The loss on Wednesday by the tournament's top seed gave Isner his earliest exit at this event in 10 appearances.
The 21-year-old Opelka saved three break points while serving at 4-5 in the third set, including two consecutively from 15/40 as he served his way out of trouble.
The unseeded Opelka also defeated Isner at the Australian Open and at the New York Open in February, where he went on to win his first ATP title.
"I was clutch on big moments in the match. First-set tie-break I played unbelievable, pretty much flawless, hit some great shots," Opelka said.
"It's so hard to play three tie-breaks with him because there's just so much pressure, there's so much stress for three hours straight. It's tough. I'm thrilled to get through."
Isner was the two-time defending champion and had reached the Atlanta final in nine of his 10 appearances.
"It's his tournament. It always will be. Definitely a tough guy to beat in Atlanta," Opelka said.
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