NEW YORK -- Even with a big early lead, Agnieszka Radwanska failed to make it to the quarterfinals at the U.S. Open.

A 6-4, 6-4 loss to 24th-seeded Ekaterina Makarova of Russia on Sunday night marked the fourth time since 2007 that Radwanska left Flushing Meadows in the fourth round. The U.S. Open is the Grand Slam tournament where Radwanska has had the least success.

Against Makarova, Radwanska went ahead 4-0, before faltering.

"She was a little bit nervous in the beginning and then (started) to play better and better and hit the ball very well," the third-seeded Radwanska said. "I didn't do anything, you know, to win that first set."

Radwanska was the runner-up at Wimbledon in 2012, and has made it to the quarterfinals at both the Australian Open and French Open. But she's never been past the round of 16 in New York, losing in the second round in 2006 and 2009-11, in addition to her fourth-round exits in 2007-08 plus each of the last two years.

She was one of only three women to reach the fourth round at every major tournament this season -- Serena Williams and Sloane Stephens were the others -- but once again had trouble on the hard courts at Flushing Meadows.

Asked why that is, Radwanska answered: "The difference is surface. Every Grand Slam is (a) different surface. I mean, the same players, the same faces. Conditions are always different everywhere, as well. It's hot or windy or sunny or cold. It's always changing."

A few hours after winning a match in Cincinnati last month, Radwanska withdrew from that hard-court tournament so she could fly home to Poland to attend her grandfather's funeral.

That trip cut short her preparation for the U.S. Open, but Radwanska said that was not an explanation for her loss to Makarova on Sunday.

Makarova had lost all three previous matches she'd played against Radwanska in straight sets. The Russian's victory Sunday allowed her to reach her third Grand Slam quarterfinal -- and first at the U.S. Open.

"I'm really happy, because I'd never beaten her. Today, I wanted to win and I fought," Makarova said. "I was a little bit in a rush at the beginning, but then it was a really good match."

Next for Makarova is a match against fifth-seeded Li Na of China, the 2011 French Open champion, who eliminated 2008 U.S. Open runner-up Jelena Jankovic 6-3, 6-0 in less than an hour Sunday night.

"For some reason, I did not feel my shots and I was late and I let her dictate the points," the ninth-seeded Jankovic said. "That was the difference."

The winner of Makarova vs. Li will play the winner of No. 1 Williams vs. No. 18 Carla Suarez Navarro in the semifinals.

Williams is the only member of that group who has won the U.S. Open, doing it four times, including a year ago.

Jankovic, though, likes Li's chances.

"The way she played tonight was at a very high level," Jankovic said. "If she continues to play like this, I think she can win the tournament."