Safin is unseeded at Flushing Meadows this year

The Argentine saved two match points before losing 6-3 7-5 2-6 3-6 7-6 (8-6) in three hours 52 minutes.

The Russian will play Olivier Rochus of Belgium in the third round on Monday.

Australia's Lleyton Hewitt, the 15th seed, reached the fourth round after a 6-3 6-1 6-2 victory over world number 23 Novak Djokovic.

Hewitt will face Frenchman Richard Gasquet for a place in the quarter-finals.

But while Hewitt enjoyed a surprisingly comfortable win over Djokovic, it was a struggle for American Andy Roddick.

The 2003 champion needed five sets to get past big-hitting Spaniard Fernando Verdasco.

Playing in front of the same crowd that earlier witnessed the end of Andre Agassi's career, Roddick came through 6-7 (5-7) 6-3 6-4 6-7 (4-7) 6-2.

He will now face Agassi's conqueror Benjamin Becker.

Home fans had a much easier time watching American fifth seed James Blake, who defeated Spain's Carlos Moya 6-4 7-6 2-6 6-3

Blake, 26, came back from 6-2 down in the second-set tie-breaker to set up a meeting with Czech 12th seed Tomas Berdych.

Rafael Nadal also had to work for his place in the last 16, edging out Wesley Moodie 6-4 7-6 (7-5) 7-6 (7-4).

But it was plain sailing for top seed Roger Federer, who strolled crushed unseeded American Vince Spadea 6-3 6-3 6-0.

The world number one, looking for his third straight US Open win, sealed victory in one hour 28 minutes.