Top-seeded John Isner lost to fellow American and qualifier Ryan Harrison in the second round Wednesday at the Sydney International tennis event, a final Australian Open tune-up.

Harrison took down his taller compatriot by a 6-4, 6-4 margin at Sydney Olympic Park Tennis Centre.

Denis Istomin, Bernard Tomic and Julien Benneteau also pulled off upsets on Wednesday. Istomin beat fourth-seeded Spaniard Fernando Verdasco 6-3, 6-3, Tomic of Australia defeated fifth-seeded German Florian Mayer 7-6 (7-4), 6-2 and Benneteau of France moved on when sixth-seeded Czech Radek Stepanek retired from their match in the first game with a back injury.

Italian Andreas Seppi, the No. 3 seed, outlasted John Millman of Australia by a 6-2, 3-6, 6-3 margin, while eighth-seeded Spaniard Marcel Granollers beat Fabio Fognini of Italy 6-2, 7-6 (7-4).

Reigning Sydney champion and 2009 runner-up Jarkko Nieminen of Finland cruised past Ivo Klec of Slovakia 6-3, 6-1. South Africa's Kevin Anderson defeated Feliciano Lopez of Spain 6-3, 6-4.

Klec replaced No. 2 seed Gilles Simon of France in the draw. Simon, the 2011 Sydney champion, pulled out due to neck injury.