Top seed Roger Federer suffered a shock straight-sets defeat against wildcard Filippo Volandri in the Rome Masters.
The Swiss world number one was humbled 6-2 6-4 by the Italian in the third round of the clay-court event.
Third seed Andy Roddick, playing in his first event since March, also bowed out after slumping 6-0 6-4 to Argentine Juan Ignacio Chela.
But Rafael Nadal beat Mikhail Youzhny 6-2 6-2 despite being taken to hospital earlier in the day after a dizzy spell.
"Everything's OK. It was just a routine check-up," said Nadal's spokesman before the Spaniard emerged on court.
Nadal extended his record-winning streak on clay to a staggering 74 matches, setting up a quarter-final with Serb Novak Djokovic, who overcame Marcos Baghdatis 6-2 7-5.
"I don't know if you can say I was playing shockingly, but I was making a lot of mistakes"
Federer's early exit means he has already suffered four defeats this year - having only been beaten five times in the whole of 2006.
The 25-year-old has not won a title in four straight tournaments - his worst run since becoming world number one in February 2004.
Against Volandri, he hit only two winners with his forehand, normally his best shot, and made 44 unforced errors to Volandri's 23.
"I don't know what's wrong. I have to analyze it myself," said Federer. "It was over too soon for me today.
"I need to get back on the practice courts instead of the match courts.
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"On clay you need to be solid, and I wasn't. I don't know if you can say I was playing shockingly, but I was making a lot of mistakes, serving badly - giving him second serves all the time.
"It sometimes happens, but usually I get through. And Volandri played well."
Federer is running out of time to find his form on clay before he begins his challenge at the French Open - the only Grand Slam title to so far elude him.
The Swiss is likely to play at the Hamburg Masters before heading to Roland Garros for the start of the year's second Grand Slam on 27 May.
"What I've done here will only sink in tomorrow. This is the best court in the world. The crowd were fabulous"
Home favourite Volandri, ranked 53rd in the world, collapsed to the ground in disbelief when Federer hit a final forehand into the net.
"What I've done here will only sink in tomorrow. This is the best court in the world. The crowd were fabulous," he said.
American Roddick, playing only his second clay-court match of the season, was broken three times in a 26-minute first set and then one break sealed his fate in the second.
"I served horribly today and that made the rest of it a little tough for me," said Roddick.
"First and foremost, though, he just played better than I did. It wasn't even close today."