Roger Federer became the latest upset victim at the Sony Ericsson Open after the World No 1 went down 6-4, 6-7, 7-6 to 16th seeded Czech Tomas Berdych in the fourth round on Tuesday.
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 said 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 No 8 Andy Roddick needed to overcome a sluggish start to book his ticket to the quarter-finals at the Sony Ericsson Open on Tuesday, 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 compatriot and Davis Cup team mate David Ferrer 7-6, 6-4.
The American fell behind 4-1, 0-40 in the first set but rallied back against Becker. After breaking serve 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 tie-breaker 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, with a victory, could possibly face Nadal in the semi-finals.
World No 4 Nadal held off Ferrer in just under two hours as the two Spaniards gave the crowd a stirring match.
The two went back-and-forth in a first set that started with Nadal leading 2-1, and finished with Ferrer losing 7-5 in the tiebreak.
Nadal squandered a 3-0 lead in the second set before breaking Ferrer in the final game for the match. He is now 9-3 against his friend with four straight victories.
"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 trailing 6-1, 1-0 against Russia's Mikhail Youzhny after injuring his sciatic nerve during the first set.
Frenchman Jo-Wilfried Tsonga also advanced after beating Spain's Juan Carlos Ferrero 6-2, 6-2.
On the women's side, Venus Williams won her 14th successive match after beating Poland's Agnieszka Radwanska.