Former champion Maria Sharapova was knocked out of the US Open by Italian Flavia Pennetta in the biggest upset of the tournament so far.

The Italian has reached the quarter-finals at Flushing Meadows twice before but pulled off one of the biggest wins of her career in a see-sawing match on the Arthur Ashe Stadium.

Pennetta, seeded 26th, raced to a 4-0 lead en route to winning the opening set. But Sharapova, who made 60 unforced errors and served 12 double faults, won the second back then recovered from 4-1 down to square the final set at 4-4.

Pennetta regained her composure to hold her serve to lead 5-4 then broke the Russian again to seal victory and advance to a fourth round clash with China's Peng Shuai

Sharapova, who won the US Open in 2006 but has not won a Grand Slam title since the 2008 Australian Open, was one of the favourites to win the crown after winning a lead-up event in Cincinnati.

But the Russian made a whopping 60 unforced errors and served 12 double faults, including two in the final game which she needed to hold to stay alive.

"It's disappointing to lose in New York. Losing isn't fun for anyone because we work to win," Sharapova said.

"We don't work to try to lose. So when we're faced with a position where we can win and we didn't in the end, it's tough."

For Pennetta, a quarter-finalist at Flushing Meadows in 2008 and 2009 who is seeded 26th, it was a moment to savour as she celebrated her victory on a baking hot day at the Arthur Ashe Stadium.

"I think this one is one of the best victories in my career, and is gonna be like this forever," she said.

"It's a good moment. I'm really happy right now but it's just a match. It's over, and I have to be focused for the next one."

Peng, the 13th seed, advanced with a 6-4 7-6 win over 19th seed Julia Goerges of Germany in an increasingly wide open women's draw.

None of the remaining players in the bottom half of the draw have won a Grand Slam title before and the only two to have played in a final are last year's runner-up, Vera Zvonareva of Russia, and Australia's Sam Stosur.

Zvonareva struggled once again, but the second seed managed to defeat Spaniard Anabel Medina Garrigues 6-4 7-5 to move into the fourth round of the year's final Slam.

Zvonareva needed two hours to defeat Garrigues for the fourth time in five career meetings.

"I was playing some good tennis and then there were a few moments where I felt like I disappeared," conceded the Russian, who committed 35 unforced errors while producing only 25 winners under sunny skies in Arthur Ashe Stadium.

Zvonareva, who was not at her best while defeating unseeded Ukrainian Kateryna Bondarenko 7-5 3-6 6-3 in her second-round match, will now face either unseeded American Irina Falconi or number 22 Sabine Lisicki of Germany.

A veteran of nine US Opens, the 26-year-old Zvonareva said she is looking to eliminate the periods where she sprays the ball around the court.

"If we take all those down moments away, I was able to raise the level of my game a little bit more today," said Zvonareva, who lost to Kim Clijsters in the 2010 final.

"Once you go deeper and deeper (into the tournament), you want that very good level and you want to improve every day."

Medina Garrigues said Zvonareva's play has been spotty but added she expected the world's number two ranked player to return to form during the US Open fortnight.

"I don't think she's in her best moment," she said. "But during the tournament, every day that passes, when she plays more matches she's going to feel better.

"She's a very tough player and she can be right back up there at the end."

While admitting she needs to become more consistent, Zvonareva said she plays well when it matters the most.

"When there are those tight moments, I really feel like that's where I'm able to produce my best tennis," she said. "That's where I'm able to really stay focused.

"It's something that comes naturally. It helps me a lot to win a lot of matches."