When it comes to Grand Slam titles, Swiss star Federer has 17, with five in a row at the US Open from 2004-2008, while Nadal owns 12 Slam crowns, including eight at the French Open and a 2010 US Open win to finish a career Grand Slam.
When it comes to their head-to-head rivalry, Nadal has won 21 times to only 10 for 32-year-old Federer and the 27-year-old Spaniard owns a 7-6 edge on hardcourts thanks to a quarterfinal victory last month at Cincinnati.
"Obviously Rafa matches up pretty well against Roger and has the belief in beating him," said Australia's Lleyton Hewitt. "If they play here, it will be a great match. I don't know if that's going to say who's the greatest, though."
The matchup would be the first on the sport's largest stage, 22,500-seat Arthur Ashe Stadium and the earliest they will have ever met in any Slam -- if it happens.
Federer, in his lowest Grand Slam seeding since 2002 at seventh, has a fourth-round match against Spanish 19th seed Tommy Robredo, who has lost all 10 matches he has played against him.
A victory would send Federer into a last-eight matchup with Nadal or 22nd seed Philipp Kohlschreiber. Nadal is 9-1 against the German, losing only last year at Halle and winning their most recent meeting at Monte Carlo in April.
Nadal is 8-2 against Federer in Grand Slam matches, 6-2 in finals, losing twice at Wimbledon before a breakthrough 2008 triumph while winning four French Open finals and a 2009 Australian Open final.
Nadal also took semfinals in 2005 at Roland Garros and last year at Melbourne. Federer won 2006 and 2007 finals at the All England Club.
Federer's 77 career titles are 18 more than Nadal, but the Spanish star has collected nine this year and is on an 18-match hardcourt win streak since ending a seven-month knee injury layoff in February.
"I think Rafa still has to win some more Grand Slams to catch Roger in terms of greatness," said Hewitt, the 2001 US Open and 2002 Wimbledon champion.
"It's hard. Roger's been around for so many years and dominated for so long, whereas Rafa dominated on clay for so long now, but he has been very good on every other surface as well, whereas Roger for a few years there hardly lost matches. It's a tough one."
Women's world number one Serena Williams was stunned to learn Nadal and Federer had never faced each other at the US Open.
"Really," she said. "Gosh, that's weird." She hedged on picking the greatest between them. "It's impossible to say which one is greater," she said. "Roger is a great player. He has done so much for the sport. He's just an unbelievable athlete and unbelievable player. He has been playing for a long time.
"Rafael, on the other hand, started younger, starting winning Grand Slams really young, and he's a great, great player as well.
"If you're going by numbers, Roger still has more Grand Slams than Rafa, so you have to go with that."
She uses the same standard to put herself and her 16 Slam titles behind the Open-era record 22 of retired German star Steffi Graf.
"I go by numbers. I don't think I'm the greatest because Steffi has way more Grand Slams than me."
Britain's Andy Murray, the defending US Open champion and reigning Olympic and Wimbledon champion, does not mind less attention than Nadal and Federer after the intense focus before he became the first British man to win a Grand Slam and a Wimbledon crown since Fred Perry in 1936.
"I haven't really noticed any of the years thinking that I'm front-page news," Murray said. "It's very different to Wimbledon, obviously, for me. In some ways it's nice but I don't really think it makes a whole lot of difference to how I play."