Isner, who bested Lleyton Hewitt last year's Newport finale and Olivier Rochus in the 2011 championship match, needed a first-set tiebreaker before going on to down fellow American Ryan Harrison 7-6 (7-0), 6-2.
Also moving on to the second round at the International Tennis Hall of Fame and Museum was France's Adrian Mannarino, who took care of American James Blake 6-4, 5-7, 6-1, and Poland's Michal Przysiezny, who got past American wild card Stefan Kozlov, 6-3, 6-7 (9-11), 6-4.
Japan's Yuichi Sugita advanced as well, besting Canadian-born Jesse Levine 7-5, 7-5.
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