Maria Sharapova fell victim to a sensational upset by Flavia Pennetta on Friday, becoming the latest women's contender to depart the US Open in the first week. The 25th-ranked Pennetta triumphed 6-3, 3-6, 6-4 to hand world number four and third seed Sharapova her first defeat in a three-set match this year. Sharapova, whose three Grand Slam titles include the 2006 US crown, was trying to build on her run to the Wimbledon final, which was her first appearance in a major final since Australia in 2008. But her bid was undone by 60 unforced errros, including 12 double faults -- the last two of them putting Pennetta on the road to victory in the final game. "It's amazing. It's one of the best victories of my career," said 29-year-old Pennetta. "We both fought a lot and in the last set I was really nervous. I was 4-1 up and I was shaking a little bit, but now I am really proud of myself." Sharapova was the latest casualty of an event in which Wimbledon champion Petra Kvitova and Roland Garros winner Li Na failed to make it out of the first round. Two-time champion Venus Williams withdrew because of illness and eighth-seeded Marion Bartoli, a French Open semi-finalist this year, was upset in the second round. Pennetta, a quarter-finalist in 2008 and 2009, will face China's 13th seed Peng Shuai, the highest-ranked player left in that quarter of the draw. Peng defeated German Julia Goerges 6-4, 7-6 (7/1). Sharapova's departure further opens the way for Russian Vera Zvonareva, the second seed who is seeking a first Grand Slam title. Zvonareva survived some shaky moments to get past Spain's Anabel Medina Garrigues 6-4, 7-5. The Russian, runner-up to Kim Clijsters last year, said she'll have to sharpen up if she wants to have a shot at a first Grand Slam title. That would also earn the kind of attention that has been focused here on Sharapova and Serena Williams, the three-time champion. "When I'm in the tournament, all I think about and all I care about is how to prepare myself the best I can for the next match," Zvonareva said of her low profile. "Those players, I think they deserve that attention. They are Grand Slam winners." Zvonareva next faces Germany's Wimbledon semi-finalist Sabine Lisicki, who beat American Irina Falconi 6-0, 6-1. On the men's side, 2009 champion Juan Martin del Potro continued to make up for lost time with a 6-2, 6-1, 7-5 victory over fellow Argentinian Diego Junqueira. A wrist injury kept del Potro from defending his title last year, but after building his ranking back up to 18 in the world he is relishing his return to Flushing Meadows. He faced a deceptively difficult task against Junqueira, a left-hander ranked 104th in the world who is from del Potro's hometown of Tandil. "It's very tough to play against a friend," he said. 'We live in the same town, we have known each other since we were five years old." If he stays the course del Potro could find world number four Andy Murray waiting in the quarter-finals. Murray reached the title match here in 2008 to become the first Briton in a Grand Slam final since 1997. Since then the pressure has been on to end Britain's wait for a Grand Slam champion, but he has been unable to do better than runner-up finishes at the last two Australian Opens. He tried to keep his latest campaign going when he tackled Dutchman Robin Haase for a third-round berth while defending champion Rafael Nadal took on French marathon man Nicolas Mahut. Mahut, best known for his epic encounter against John Isner at Wimbledon last year, rallied from two sets down to get past qualifier Robert Farah in the first round. Nadal was confident that at least he wasn't in for a 11-hour match such as Mahut and Isner served up at Wimbledon. "That's not going to happen," he said. Rising US talent takes center stage in the night session on Arthur Ashe Stadium, where 18-year-old Jack Sock was to take on America's former world number one Andy Roddick. Christina McHale, the 19-year-old from nearby New Jersey who is poised for a Cinderella run after toppling Bartoli, was to take on 25th seed Maria Kirilenko of Russia.