John Isner of the United States lost to David Goffin 7-6 (2), 4-6, 6-4 Wednesday in the second round at the Valencia Open.
Isner had 21 aces but it wasn't enough against his Belgian opponent, who has improved in the rankings to 45th from No. 175.
Isner has gone 4-5 since winning at Winston-Salem in August. The loss hurts his bid to qualify for the World Tour Finals next month, with only the Paris Masters left to play before the season-ending event.
Seventh-seeded Marin Cilic joined Goffin in reaching the quarterfinals with a 6-1, 6-4 victory over Fernando Verdasco, with fellow Croatian Ivan Dodig also winning his second-round match, a 6-1, 3-6, 6-2 win over Australian veteran Lleyton Hewitt.
Gilles Muller of Luxembourg knocked off No. 8-seeded Milos Raonic in the first round, edging the Canadian 7-5, 7-6 (1). Also, reigning champion Marcel Granollers of Spain also beat Czech qualifier Jan Hajek 7-5, 6-4 to advance to the second round.