The dominant duo of modern tennis may have met 37 times in their careers but never in New York.
Federer and Nadal look destined for long-awaited showdown at injury-hit US Open
Their rivalry has stretched 13 years and 37 matches but Rafael Nadal and Roger Federer have never met at the US Open, an anomaly which seems certain to be corrected after a host of rivals limped out of contention.
Nadal, back on top of the world rankings for the first time in three years, is a two-time winner in New York, his 2010 and 2013 titles forming part of his 15-grand slam portfolio which was embellished by a record 10th French Open in June.
Federer, the five-time US champion from 2004-2008, is bidding for a 20th major and third of the year after capturing the Australian Open and Wimbledon titles.
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Victory in the men's final on September 10 would also make the 36-year-old Swiss the oldest US Open champion of the modern era and oldest overall since Bill Tilden in 1929.
The path to the title for Nadal and Federer has been eased. World No 2 Andy Murray, the 2012 champion, withdrew on Saturday after failing to recover from a hip injury.
Two-time winner Novak Djokovic has already shut down his season to recover from an elbow injury while defending champion Stan Wawrinka faces knee surgery.
With Kei Nishikori, the 2014 runner-up, and Milos Raonic also injured, five of the current world top 11 will be missing when the tournament starts on Monday.
However, for tennis romantics, Murray's withdrawal came after the draw was made leaving top seed Nadal and third-seeded Federer in the same half, thereby ruling out a collision in the final.
Nadal, 31, heads to New York on the back of a quarter-final loss to Nick Kyrgios in Cincinnati and a Montreal last-16 defeat to Canadian teenager Denis Shapovalov. The Spaniard said he would rather not have Federer in his semi-final path, should they get that far.
"I prefer to play against another player, an easier one if it's possible," said Nadal, who has not got past the fourth round since 2013 and starts his campaign against Dusan Lajovic, the world No 84 from Serbia.
"Finals are more special than semi-finals. But anyway, meeting him here in semi-finals, if that happens that will be something great and amazing."
Federer, meanwhile, is looking to move beyond Pete Sampras and Jimmy Connors by claiming a sixth US Open and reach a first final in the city since his sensational 2009 loss to Juan Martin del Potro.
His record-blazing eighth Wimbledon title in July was followed by a Montreal final defeat to Alexander Zverev and a pull-out from Cincinnati with a back injury.
But with a 2017 record of five titles, 35 match wins and just three losses, Federer remains the sentimental favourite.
"It would be fun for everybody involved. We have our work cut out there. But, you know, I'd love to play Rafa here in New York," said Federer, who missed the 2016 US Open to rest a knee injury.
Federer starts his bid for a sixth title against US teenager Frances Tiafoe, the world No 71 who shocked Zverev in Cincinnati.
With Murray, Djokovic, Wawrinka - with 18 grand slams between them - Nishikori and Raonic all missing, the tournament should also present the perfect opportunity for the widely-touted 'NextGen' to step up.
Zverev, the world No 6, downed Federer for the Montreal title but slumped first time out in Cincinnati to Tiafoe. The German has never got beyond the fourth round of a major and was a second-round loser in New York in 2016.
Kyrgios, the runner-up in Cincinnati, made the quarter-finals at the Australian Open in 2015 and Wimbledon in 2014 but his US Open best is a run to the third round.
World No 8 Dominic Thiem, a semi-finalist at Roland Garros in 2016 and 2017, has never got beyond the last 16 in New York.