Less than 24 hours after his upset of Federer, Roddick endured a drubbing against Monaco, 7-5, 6-0.
Monaco, a patient baseliner seeded 21st, was unfazed by Roddick's big serve, and the match became a succession of long rallies. Roddick began to look weary as the match progressed and stumbled after several shots as the match slipped away.
Roddick said he's not in peak condition after being sidelined by right hamstring and right ankle injuries earlier this year.
"I just didn't have it physically," he said. "I got to about 4-all, and I was -- you know, I'm out of shape. That's it."
The loss was a big comedown after Roddick beat Federer for only the third time in 24 tries, temporarily silencing critics who say he should consider retirement.
Roddick's ranking has slipped to 34th, his lowest since 2001. He might return to the top 30 next week, and said his game is headed in the right direction entering the clay-court season.
"My tennis has come around a long way in the last two weeks, maybe three weeks," he said. "Now I feel good enough where I feel like I can put in the work away from the court and get my legs back under me as far as strength and fitness."
The victory was by far Nadal's most taxing of the tournament, and he took a medical timeout late in the opening set for treatment of his troublesome left knee. Even so, he's one round closer to his first Key Biscayne title.
"I am not probably in perfect condition today with the left knee," he said. "But the important thing is to try to win as many matches as possible. For me this is an important tournament, and every victory has very, very big value for me, especially without being perfect."
Nadal, a three-time runner-up at Key Biscayne, lost the final last year to Novak Djokovic, and they could meet again Sunday. The top-ranked Djokovic reached the final eight by beating No. 17-seeded Richard Gasquet 7-5, 6-3.
No. 8 Mardy Fish edged No. 12 Nicolas Almagro 6-3, 6-7 (2), 6-3. Fish was relegated to the grandstand court for the third consecutive match, even though he's the top-ranked American man, but the slight didn't faze him.
"I certainly want to play on stadium court," Fish said. "But they've got to put someone out on the grandstand, and who's that going to be? Are you going to put Federer out there, or Djokovic, or Nadal, or Serena? I'm not going to go ahead of those guys as far as people coming to watch them play. You've got to go where you've got to go."
Monaco's victory spoiled a potential quarterfinal matchup between former high school teammates Fish and Roddick -- not that fans seemed disappointed. Thanks to Miami's large Argentine population, Monaco enjoyed strong support from the stadium crowd, with fans singing in Spanish between points.
The victory by the 27-year-old Monaco wasn't a shock. He has played well this year, winning Vina del Mar last month for his fourth career title and first since 2007.
Roddick had only eight winners and 37 unforced errors. He hit just two aces and lost serve five times.
"When you have to make a quick recovery, it will expose you if you're not in shape," he said.
Nadal's not at a physical peak, either. He has been bothered by his knee since Indian Wells, where he lost to Federer in the semifinals two weeks ago.
Nine games into his match against Nishikori, Nadal called a medical timeout and had a trainer tape his leg. That's when the momentum swung.
In the next game, Nadal took the opening set with a service break when Nishikori sailed an easy forehand long. The Spaniard broke again as he raced to a 3-love lead in the second set.
"At the end of the first set, I felt that I started to win my serves easier than him," Nadal said. "I had more the control of the game."
Nadal improved to 16-3 this year. He's seeking his first tournament title since the 2011 French Open.
Information from The Associated Press was used in this report.