Roger Federer became the latest upset victim at the Sony Ericsson Open after the world number one went down 6-4 6-7 7-6 to 16th seeded Czech Tomas Berdych in the fourth round on Tuesday.
The 16-times grand slam champion had beaten Berdych in eight of their previous nine encounters but paid the penalty for an error-strewn display in which the Swiss top seed could only convert two of 12 break point opportunities.
Federer's defeat means the top three men's seeds have all been knocked out after Serbia's Novak Djokovic and Britain's Andy Murray both suffered shock defeats earlier in the tournament.
"It was a tough match. Look, it's no secret I've struggled the last, what is it, five matches I've played here in the states," Federer told reporters after his second early exit in a row since winning the Australian Open in January.
"It's disappointing, I think, my performance overall, if I've got to analyse right now after the match, but I fought as much as I could with my game having issues at the moment.
"Definitely lacking timing. I don't know where that comes from because I played so nicely in Australia. Maybe the sickness (a lung infection in February) did take it out of me more than I thought."
Berdych cautioned against getting too carried away with one of the best wins of his career.
"To beat the number one player in the world, the best player so far is a great feeling. But still, it was not a final. There is another match waiting next day, another really tough opponent," he said.
Earlier, world number eight Andy Roddick needed to overcome a sluggish start to book his ticket to the quarter-finals while Rafa Nadal also advanced after being tested early in his match.
Roddick, fresh from finishing runner-up at Indian Wells, beat Germany's Benjamin Becker 7-6 6-3 while Nadal brushed past Spanish compatriot and Davis Cup team mate David Ferrer 7-6 6-4.
The big-serving American fell behind 4-1, 0-40 in the first set but rallied back against Becker. After breaking to get to 4-3, Roddick served a 134 mph (214kph) ace as he tied it 5-5.
It was downhill from there for the unseeded Becker as Roddick won the tiebreak 7-4 before easing through the second set.
"He came out aggressive and ready to play from the first ball," Roddick, who limited his unforced errors to 15, told reporters. "I was maybe looking to work my way into the match a little bit more than he afforded me."
Roddick will face Spain's Nicolas Almagro in Wednesday's quarter-final and could possibly face Nadal in the semi-finals.
World number four Nadal is now the highest-ranked player left in the tournament after he held off Ferrer in just under two hours as the Spaniards gave the crowd a stirring spectacle.
After edging a tight opening set, Nadal squandered a 3-0 lead in the second set before breaking Ferrer in the 10th game to seal match, improving his record to 9-3 against his friend with his fourth straight victory.
"It was a match of highs and lows," Nadal said. "I started the second set well then played the next three games poorly, but I accepted it and kept working and waiting for my opportunity."
American Mardy Fish retired when trailing 6-1 1-0 against Russia's Mikhail Youzhny after injuring his sciatic nerve during the first set, while Frenchman Jo-Wilfried Tsonga advanced after beating Spain's Juan Carlos Ferrero 6-2 6-2.
On the women's side, third seed Venus Williams won her 14th successive match after beating Poland's Agnieszka Radwanska 6-3 6-1 in their quarter-final match.