Former world number one Rafael Nadal has endured an injury-plagued campaign that forced him to miss two and a half months of competitive tennis, but he returned to action at the Rio Olympics, and won his second Olympic gold medal with Marc Lopez in the doubles for Spain.
Denis Istomin is languishing at 107 in the world, and the Uzbek has been ranked as high as 33, however, Istomin has never reached the quarterfinals of a Grand Slam tournament with fourth round finishes at Wimbledon in 2012, and the US Open in 2013, his best results at Slams.
Nadal's a two-time US Open champion, overcoming fellow two-time champion Novak Djokovic in both finals in 2010 and 2013. Currently ranked at five in the world, he is seeded fourth at Flushing Meadows and hopes to go far once again.
Istomin has only won one title to date in his career at the Aegon Open on the lawns of Nottingham last year, and the 29-year-old will be a tough test for the 14-time Grand Slam champion.
Nadal's notable results leading up to Flushing Meadows
The 30-year-old Spaniard has been inactive throughout most of the hard court season, but he has recorded mixed results this year on this surface.
Djokovic overpowered Nadal in their meeting in the final of Doha at the start of the year, and compatriot Fernando Verdasco ousted him in the first round of the Australian Open, which was a bitterly disappointing result for the 2009 champion in Melbourne.
Despite a closely contested first set, the 14-time Grand Slam champion was no match for Djokovic at the BNP Paribas Open in Indian Wells, losing in straight sets once again in the semifinals, and he was unable to back up his good run in the Californian Desert due to suffering a fever in his match with Damir Dzumhur that led him to retire in Miami.
The Spaniard claimed two titles on his beloved clay court surface at the Monte Carlo Rolex Masters for the ninth time dispatching Gael Monfils in the final, followed by a triumph in Barcelona for the ninth time over two-time defending champion Kei Nishikori.
Unfortunately, a career-threatening wrist injury intervened which forced the nine-time French Open champion to withdraw from the second Grand Slam tournament of the year, following the conclusion of his second round match that left him in tears.
However, the 2008 Olympic gold medalist in the singles returned to competition at the Rio Olympics, and it was unknown to see how the left-hander would do.
It was a successful tournament for Nadal, and exceeded a lot of people's expectations by finishing fourth in the singles event, and claimed a second Olympic gold medal in the doubles event with compatriot Marc Lopez.
The schedule was heavy in Rio, and an exhausted two-time Olympic gold medalist travelled to Cincinnati, but was out of sorts and completely outplayed by Borna Coric in the third round.
Istomin's notable results leading up to the US Open
Istomin is also known as "Denis the Menace" and he encountered a woeful start to his ATP World tour campaign in 2016 by losing in the first round in seven consecutive tournaments, and it looked like it was going to be eight in a row until he came back from a set down to defeat Borna Coric in the first round of the Miami Open.
2012 US Open champion Andy Murray defeated him in straight sets in the second round, Juan Monaco ended his French Open campaign in the first round, Radek Stepanek defeated him in Stuttgart, and Damir Dzumhur dished out a three-set loss to end his title defence in Nottingham at the first hurdle.
At Wimbledon, Istomin recorded his best victory in 2016 by coming back from two sets to love down to oust last year's US Open quarterfinalist Kevin Anderson in the opening round, and Nicolas Almagro in the second round but this year's French Open quarterfinalist David Goffin prevented him from reaching the fourth round at SW19 for the second time in as many years.
The Uzbek represented his country for the second time at the Olympics, unfortunately, he was only able to win two games in his first round match with David Ferrer.
Their history
Nadal and Istomin have played against each other on four occasions, and they have met on all three surfaces with the two-time US Open champion boasting a flawless 4-0 advantage.
Their first encounter was at the Queen's Club in 2010, and Istomin was able to win his solitary set against Nadal in this meeting, in a tight 7-6, 4-6, 6-4 meeting on the grass courts of London.
This will be their second meeting at the US Open as they met in the second round in 2010 with the former world number one winning 6-2, 7-6, 7-5, and went on to win his first title in New York which completed his Career Grand Slam and third successive Grand Slam triumph.
At the French Open in 2012, the nine-time champion thrashed Istomin 6-2, 6-2, 6-0 in the second round and went on to win his seventh title in Paris.
Nadal won their most recent meeting in the third round of the Miami Open in 2014 and once again, Istomin struggled to contain the Spaniard by losing 6-1, 6-0.
Who wins?
The fourth seed in Flushing Meadows has benefitted from the withdrawal of rival and five-time champion Roger Federer, but he is placed in the top half of the draw with his rival and defending champion Novak Djokovic and they are projected to meet in the semifinals.
Istomin likes to play defensively on the baseline by trying to wear down his opponents, however, his forehand and backhand are attackable but he is comfortable on the baseline as he is speedy around the court.
The 29-year-old doesn't possess a good serve but he mixes up his serve with a top spin and slices it, however, this perfectly plays into the hands of Nadal because the Spaniard is a good returner, and likes to dictate play.
Nadal hasn't reached a Grand Slam quarterfinal this year, and he will be hoping to go on a deep run in New York.
The lefty's serve works well on the hard courts at the US Open along with his forehand down the line shot, and although he doesn't use it much, he could throw in a drop shot to get Istomin off the baseline.
This is the third match scheduled in the Arthur Ashe Arena following the first round women's match between reigning Australian Open champion Angelique Kerber and Polona Hercog.
The winner of this first round match will face the winner of Andreas Seppi and Stephane Robert in the second round. Nadal will be hoping for another straightforward match with Istomin, and it should be a matchup to entertain the crowd.
Prediction: Nadal in straight sets