Uniondale - Reilly Opelka ousted No 5 seed and 2018 semi-finalist Adrian Mannarino of France 2-6, 7-6 (7/5), 6-4 on Tuesday at the New York Open.
Opelka upset fellow American John Isner in January at the Australian Open.
Isner is the No 1 seed this week in the indoor tournament on Long Island and plays his opening match on Wednesday.
In other first-round matches at the Nassau Coliseum, American Ryan Harrison swept Canada's Peter Polansky 6-3, 6-4; Christopher Eubanks of the USA beat Adrian Menendez-Maceiras of Spain 6-4, 7-6 (7/4); Guillermo Garcia-Lopez of Spain ousted Australian Alexei Popyrin 7-6 (8/6), 6-3 and Jason Jung of Taiwan beat India's Ramkumar Ramanathan 6-3, 3-6, 6-1.
Results from New York Open ATP tournament on Tuesday (x denotes seed):
Christopher Eubanks (USA) bt Adrián Menéndez (ESP) 6-4, 7-6 (7/4)
Guillermo García-López (ESP) bt Alexei Popyrin (AUS) 7-6 (8/6), 6-3
Reilly Opelka (USA) bt Adrian Mannarino (FRA x5) 2-6, 7-6 (7/5), 6-4
Ryan Harrison (USA) bt Peter Polansky (CAN) 6-3, 6-4
Brayden Schnur (CAN) bt Jack Mingjie Lin (CAN) 6-1, 6-3
Jason Jung (TPE) bt Ramkumar Ramanathan (IND) 6-3, 3-6, 6-1