French fifth seed Jo-Wilfried Tsonga became the first major casualty of the US Open on Thursday while women's second seed Agnieszka Radwanska teetered on the brink before staging a dramatic comeback.

Tsonga, who made the quarter-finals in 2011, slumped to a 6-4, 1-6, 6-1, 6-3 second-round defeat to unheralded Slovak Martin Klizan.

The flamboyant, shot-making Frenchman had come into the final Grand Slam event of the season in a fog of injury and form worries, summed up by having to skip the Cincinnati event after cutting his knee on a fire hydrant.

His defeat was good news for British third seed Andy Murray, the Olympic champion, who had been due to face the Frenchman in the semi-finals.

Tsonga blames self

"Today I was not in good shape. I didn't play good tennis," said the 27-year-old Tsonga.

"It seemed like I couldn't hit the ball hard enough to put my opponent out of position. I'm not a machine. Sometimes I'm tired; sometimes not. Sometimes in good shape; sometimes not."

Left-hander Klizan, the world 52, progressed to the third round of a Grand Slam for the first time and will tackle either 32nd seed Jeremy Chardy of France or Australia's Matthew Ebden.

Klizan only won his first career Grand Slam match this year at the French Open and has spent most of his time on the second-tier Challenger tour where he won four titles this season.

But he shrugged off that inexperience on Thursday, firing 32 winners to help offset the 42 unforced errors he sent down in a positive display of attacking tennis.

"He's like, number six in the world and I beat him," said Klizan. "This is the best result in my career."

Radwanska manages to win

Radwanska, who was Wimbledon runner-up last month, almost suffered a fourth successive US Open second-round exit before fighting back from a set and 3-1 down to beat Spain's world number 39 Carla Suarez-Navarro 4-6, 6-3, 6-0.

Polish star Radwanska goes on to face Serb 30th seed Jelena Jankovic, the 2008 runner-up, who made the third round with a 6-4, 6-2 win over Spain's Lara Arruabarrena-Vecino.

But the 23-year-old Pole endured a roller-coaster afternoon on the Grandstand court, slipping to a set and 3-1 down before reeling off 11 games in a row to take victory.

In a brutally one-sided final set, Suarez-Navarro won only eight points.

No other upsets

Elsewhere on Thursday, Spanish men's 11th seed Nicolas Almagro fought back to beat Philipp Petzschner 6-3, 5-7, 5-7, 6-4, 6-4 with the German's challenge undone by 62 unforced errors.

Japan's 17th seed Kei Nishikori also made the third round with a 6-2, 6-2, 6-4 win over American qualifier Tim Smyczek.

American 23rd seed Mardy Fish, a quarter-finalist in 2008, beat Russia's Nikolay Davydenko, a semi-finalist in 2006 and 2007, in a gruelling five-setter.

His 4-6, 6-7 (4/7), 6-2, 6-1, 6-2 win was the 10th comeback victory from two sets-to-love down in the men's tournament this year.

Ana Ivanovic on painkillers

Serbia's Ana Ivanovic reached the third round, but admitted she needs to take painkillers every morning to see her through the season's last Grand Slam tournament.

The 12th-seeded Serb, who has never got beyond the fourth round in New York, made the last 32 with a 6-2, 6-2 win over Sofia Arvidsson of Sweden.

But the 2008 French Open champion is still bothered by a right foot injury which forced her out of the Cincinnati tournament on the eve of the US Open.

"I still have to take a handful of pills every morning," said the 24-year-old.

Ivanovic goes on to face either America's Sloane Stephens or German qualifier Tatjana Malek for a place in the last 16.

Later Thursday, five-time US Open champion Roger Federer, bidding to become the first six-time US Open winner in the Open era, tackles 32-year-old German Bjorn Phau.

Both Williams sisters also take to the court looking to reach the third round.