Comeback queen Serena Williams, a three-time winner, and five-time men's champion Roger Federer reached the US Open last 16 on Saturday as the Flushing Meadows injury curse claimed a record 18th victim.

Williams, who missed last year's tournament at the start of an 11-month injury and life-threatening illness lay-off, defeated Belarusian fourth seed Victoria Azarenka 6-1, 7-6 (7/5).

The 13-time Grand Slam champion, seeded just 28th, next faces either former world number one Ana Ivanovic of Serbia or US wildcard Sloane Stephens for a place in the quarter-finals.

In a tournament missing defending champion Kim Clijsters, and which saw Maria Sharapova, French Open champion Li Na and Wimbledon winner Petra Kvitova all failed to reach the second round, Williams looks the hot title favourite.

Federer reached the fourth round for a 30th straight major with a 6-3, 4-6, 6-4, 6-2 win over Croatia's 27th seed Marin Cilic.

The third-seeded Swiss plays either Argentina's Juan Monaco or Tommy Haas of Germany for a place in the quarter-finals.

"It was a tough match. Coming in I knew it was going to be tricky, and I'm happy that I was able to counter his pace and his good play," said Federer.

"In the third set, at the beginning, was a key moment because he had momentum on his side. I was not returning and serving exactly the way I wanted, but I was able to turn it around and finished strong."

Wozniacki, the runner-up to Clijsters in 2009, and still searching for an elusive first Grand Slam title, made the last 16 with a 6-2, 6-4 victory over America's world number 103 Vania King.

The Dane next faces either 15th-seeded Russian Svetlana Kuznetsova, the 2004 champion, or Uzbekistan's Akgul Amanmuradova.

"It's great to be through. I was fighting and getting a lot of balls back. It was windy out there so it was quite difficult to play," said Wozniacki.

Meanwhile, Czech ninth seed Tomas Berdych and Marcel Granollers, the Spanish 31st seed, took the tournament injury toll to a record 18 when they quit their third round matches.

Berdych was suffering from a right shoulder injury and needed treatment at the end of the first set against Serbia's Janko Tipsarevic, which he lost 6-4, and then called it quits when he was down 5-0 in the second.

Granollers was trailing Spanish compatriot and 2003 runner-up Juan Carlos Ferrero 6-1, 4-3 when he brought proceedings to a halt with a stomach strain.

Tipsarevic and Ferrero will meet for a quarter-final place.

Berdych, 25, said he first felt the injury in his Cincinnati Masters quarter-final win over Federer two weeks ago before it caused him to quit his semi-final against Novak Djokovic.

"I already knew there was a problem. I had it in Cincinnati, so it was a case of just trying," he said.

Also going through on Saturday was 2010 French Open champion Francesca Schiavone, the Italian seventh seed who saved a match point before defeating South Africa's Chanelle Scheepers 5-7, 7-6 (7/5), 6-3.

Schiavone will face Russian 17th seed Anastasia Pavlyuchenkova who beat Serbian 11th seed Jelena Jankovic, the 2008 runner-up, 6-4, 6-4.

German 10th seed Andrea Petkovic made the last 16 for the second successive year with a 6-4, 6-0 win over Italian 18th seed Roberta Vinci 6-4, 6-0.

She will face Carla Suarez Navarro, who put out fellow Spaniard Silvia Soler-Espinosa 6-0, 6-4.

Later Saturday, men's top seed Djokovic eyes his 60th win in 62 matches this year when he tackles Russia's Nikolay Davydenko, a semi-finalist in 2006 and 2007.

Djokovic has lost just three games in his first two rounds as he bids to win a first US Open title and add to the Australian Open and Wimbledon crowns he has already collected in his record-breaking year.