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

Sharapova, seeded third, struggled in becoming the first big casualty of this year's championship, losing 6-3 3-6 6-4 in two and a half hours.

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 center court.

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.