KEY BISCAYNE, Fla. -- Andre Agassi's reign on Key Biscayne ended when he turned tentative Tuesday.
Five times, Agassi held a set point with a chance to pull even against Agustin Calleri. Each time, Agassi had a look at a second serve but managed only a meek return and lost the point.
The squandered opportunities proved costly for the three-time defending champion, upset 6-2, 7-6 (2) in the fourth round of the Nasdaq-100 Open.
"I missed some chances," Agassi said. "I needed to step it up and play to his standard, and I didn't do that."
Agassi had won 19 consecutive matches in the tournament, which he has won six times. He was bidding for his 800th career match victory.
Instead, the 27-year-old Calleri earned a win he ranked with the best of his career. The Argentine served poorly but dominated from the baseline, repeatedly skipping shots off the line. He hit 47 winners, many on backhands into the corner that Agassi didn't even try to chase.
"I wish somebody would tell me why he hit the ball so well," the fourth-seeded Agassi said. "He was just playing too good for a long stretch of time out there."
On the women's side, top-seeded Serena Williams won the tournament's most lopsided quarterfinal since 1996, beating Jill Craybas 6-0, 6-1.
In other men's play, second-seeded Andy Roddick reached the quarterfinals for just the second time. He lost only 10 points on his serve and needed barely an hour to eliminate unseeded Guillermo Canas 6-3, 6-3.
Spanish 17-year-old Rafael Nadal was unable to summon the shotmaking that helped him upset top-ranked Roger Federer in the third round. Nadal lost to No. 21-seeded Fernando Gonzalez 7-6 (1), 4-6, 6-2.
No. 3 Guillermo Coria won the final five games to overtake qualifier Julien Benneteau 7-6 (3), 2-6, 7-5. Nicolas Kiefer also reached the quarterfinals by beating No. 12 Sebastien Grosjean 6-4, 6-2.
Todd Martin committed 40 unforced errors and lost a matchup of unseeded players to Andrei Pavel, 7-6 (5), 7-6 (1).
Agassi trailed from the start and lost the first set in 33 minutes. In the second set, he rallied from a break down twice, took a 5-4 lead and held five set points in the next game.
"I was lucky," Calleri said. "Agassi missed a couple of shots by himself without me forcing him to make the error."
Long touted as the best returner in the game, Agassi conceded he should have been more aggressive on at least a couple of the set points.
"The ball was sort of sitting there, and it was probably an easier shot than I was making it," he said. "But you're telling yourself not to do anything too stupid because he's living on the edge out there, hitting the ball real big. You just feel like at any point he could start missing."
Instead, the 20th-seeded Calleri saved some of his best work for the tiebreaker. He dropped one last forehand on the baseline to reach match point, and when Agassi sent his final serve long for a double fault, Calleri sank to his knees in jubilation.
The victory was just his second over a top-10 player on a hardcourt. He ranked the win with one against Juan Carlos Ferrero in Davis Cup as the best of his career.
"I was glad that it was just two sets," Calleri said. "We played in a very intense manner during the whole match. If it was three sets, probably it would have been difficult."
Williams, who returned from an eight-month layoff last week, won the first 10 games and needed just 55 minutes to advance to Thursday's semifinals. She'll play the winner of the match Tuesday night between No. 25 Eleni Daniilidou and No. 29 Karolina Sprem.
The Williams sisters remain on course to resume their sibling rivalry in the final Saturday. Venus Williams faces No. 5 Elena Dementieva in the quarterfinals Wednesday.
Craybas, the lone unseeded women's quarterfinalist, drew a big cheer when she finally won a game. The former NCAA champion's breakthrough came on an errant backhand by Williams, who shrieked in reaction to the rare mistake.
Williams smacked five aces and 22 winners. She has won 16 consecutive matches at Key Biscayne, including the finals in 2002 and 2003.
The tournament is Williams' first since knee surgery after winning her sixth Grand Slam title at Wimbledon in July.