ROME -- Rafael Nadal became the first player to break John Isner's serve in nearly a month, and he did it twice in a 6-4, 6-4 win to reach the Italian Open quarterfinals on Thursday.

Andy Murray and Serena Williams, meanwhile, withdrew from the last big warm-up tournament before the French Open, which starts in 10 days.

Murray cited fatigue following consecutive clay titles in Munich and Madrid, while Williams said she has a right elbow injury.

The 16th-seeded Isner held serve in 84 consecutive games stretching back to his last meeting with Nadal on April 16 in the Monte Carlo Masters, when Nadal broke him in the third set and went on to win.

This time, Nadal broke to take a 3-2 lead in the first set with a forehand winner that landed on the line on his first break point. Then the Spaniard produced a whipping forehand return pass up the line off Isner's second serve to go up 5-4 in the second, and quickly closed it out from there.

"When I had chances I (took advantage)," Nadal said. "My serve was perfect the whole match. I played with (few) mistakes."

Nadal will next face eighth-seeded Stan Wawrinka, who beat Dominic Thiem of Austria 7-6 (3), 6-4.

Roger Federer struggled only to close out a 6-3, 7-5 win over big-serving South African Kevin Anderson. Anderson served 14 aces to Federer's four, and matched the 17-time Grand Slam champion with 22 winners, but never really put Federer under pressure.

Also advancing was seventh-seeded David Ferrer, who defeated Guillermo Garcia-Lopez 6-1, 6-3. Ferrer's quarterfinal opponent will be David Goffin of Belgium, who advanced when Murray pulled out.

In women's action, second-seeded Simona Halep routed 1999 Rome champion Venus Williams 6-2, 6-1; two-time champ Maria Sharapova eliminated Serbian qualifier Bojana Jovanovski 6-3, 6-3; and Carla Suarez Navarro defeated Eugenie Bouchard 6-7 (2), 7-5, 7-6 (7).

American qualifier Christina McHale made the last eight when Serena Williams withdrew.

Nadal won a higher percentage of points on his first serve than the 2.08-meter (6-foot-10) Isner -- 90 to 82 per cent.

A seven-time Rome champ, Nadal also won virtually all of the long rallies against the American, who has given him trouble in the past, including on clay.

On Monday, Nadal dropped out of the top five in the ATP rankings for the first time in 10 years -- falling to No. 7. Struggling to get back to his best after a wrist injury and an appendectomy last season, Nadal has lost four times on clay this year -- something he hasn't done since 2003.

But he remains optimistic.

"It seems like I'm having much more good days than bad days," Nadal said.

Murray dominated Nadal in Sunday's Madrid Open final, a week after taking his first clay title in Munich.

"I'm tired. My body is tired," Murray said. "It's completely normal, and I think acceptable to feel like that after the last few weeks."

Serena Williams is trying not to make the same mistake as last year and let an injury affect her chances at Roland Garros.

"We have to make the right decisions for the future, not for now," Williams said. "You know I hate, hate quitting, and this isn't quitting, it's just making a good decision.

"I was really injured last year, actually, and ended up taking like five days off before Paris and practicing just a day or two before the tournament started," added Williams, who lost in the second round. "And entering a Grand Slam, you never want to enter it like that, especially as defending champion."