PARIS (AP) -- Roger Federer finally cracked under the unrelenting serve of John Isner, losing 7-6 (3), 3-6, 7-6 (5) to the 13th-seeded American in the third round of the Paris Masters on Thursday.
The 17-time Grand Slam champion looked like he might grind out a win, saving all six break points and fighting back from 6-2 down in the decisive tiebreaker. But the Swiss star's resistance ended when Isner - who had 27 aces - hit a looping serve to his backhand.
"It's tough going out of a tournament without losing your serve," the third-seeded Federer said.
Fourteen-time major winner Rafael Nadal, seeded seventh, almost followed him through the exit door, saving a match point in a 4-6, 7-6 (6), 6-2 win against 11th-seeded Kevin Anderson of South Africa.
"Very tough match, he served amazing. I feel very lucky to be through," Nadal said. "This type of match a couple of months ago I would not have had chances to win. In terms of mentality I (am) more calm."
Top-ranked Novak Djokovic was not at his best, either, advancing to the quarterfinals by beating 14th-seeded Gilles Simon 6-3, 7-5.
But Federer's defeat came as a genuine surprise.
Having won his sixth title of the season and 88th of his career at the Swiss Indoors last Sunday, and after racing past Italian Andreas Seppi in just 47 minutes on Wednesday, he was full of confidence.
Federer held a 5-1 career lead over Isner, beating him in the U.S. Open fourth round this year.
"I thought he did very well today when he needed it," Federer said. "I thought he served great."
Federer briefly needed treatment at the start of the second set because of a sore arm, but quickly recovered, insisting "it didn't affect me in the third set and it's not serious."
Isner called it one of the "top five" wins of his career.
"He's an incredible player, obviously. My favorite player and the greatest of all time," Isner said. "It was a huge win for me. I'm very proud."
Isner saved a break point in the fifth game of the third set with a deft backhand volley.
"That arguably saved the match for me," said the 30-year-old, who next faces No. 8 David Ferrer of Spain after he rallied to beat Bulgarian Grigor Dimitrov 6-7 (4), 6-1, 6-4.
On Wednesday night, Anderson finished his second-round, three-set match against Austrian Dominic Thiem at 12:26 a.m. after spending 2 hours, 45 minutes on court.
This time he finished just as the clock struck midnight after 2 hours, 27 minutes on court.
But it could have been over quicker.
At 6-5 up in the tiebreak, and with Nadal on second serve, Anderson failed to finish a long rally concluded by Nadal's risky yet brilliant forehand winner into the top left corner.
The Spaniard celebrated with a yell and a fist pump, clinched the set when a rattled Anderson sent a forehand into the net, and immediately broke Anderson in the third set before holding for 2-0.
Anderson fought back, however, and Nadal needed to save six break points in a grueling fourth game lasting 12 minutes.
That proved to be the end of Anderson's resistance.
After Nadal broke him again for 5-2 and clinched victory with a crisp forehand winner, the relief was evident as he tilted his head back in relief before shaking hands with the South African.
Nadal next faces No. 4 Stanislas Wawrinka of Switzerland, who beat Serbian Viktor Troicki 6-4, 7-5.
Earlier, Djokovic extended his winning streak to 19 matches despite dropping his serve five times.
"In sport there are days when you just lose your rhythm. You're trying a bit too much and you lose a bit of confidence," Djokovic said. "It was frustrating ... It hasn't happened to me for a long time."
The 10-time Grand Slam champion now plays No. 5 Tomas Berdych of the Czech Republic, who beat No. 9 Jo-Wilfried Tsonga of France 6-3, 6-4.
No. 2 Andy Murray had the easiest path to the last eight, routing David Goffin 6-1, 6-0 in a prelude to the Davis Cup final later this month.
Murray, who lost only eight points on his serve and broke the 16th-seeded Belgian five times, opens Friday's quarterfinals against No. 10 Richard Gasquet.
The Frenchman advanced when Kei Nishikori of Japan retired while trailing 7-6 (3), 4-1.