Last year, the pair played the longest match in tennis history, with Isner winning 6-4, 3-6, 6-7 (7), 7-6 (3), 70-68 in a first-round match at the All England Club that lasted 11 hours, 5 minutes stretched over three days. A gasp followed the announcement at Friday's draw, followed by laughter.
"It's going to be pretty nuts," Isner said Friday. "I couldn't believe it. I joked with him earlier in the week, last week, and said, 'Watch us play each other.' And he said, 'No, there's no way. That's not even funny.' "
The two players have become good friends since their historic encounter a year ago. They were to practice against each other Saturday, but canceled those plans as soon as they found out the rematch was on.
"We might do dinner (afterward)," Isner said. "We're really good friends now, but obviously we both want to win. But we're going to enjoy it and laugh at it at the same time."
The probability that Isner and Mahut would draw each other again in this year's Wimbledon first round -- given that they were both unseeded -- was 0.7 percent, which is 7 in 1,000 or about 1 in 143, according to ESPN Stats & Information.
It seemed all the more amusing considering Isner's tweet earlier
in the day: "anyone seen the wimby draw? Who do I play?"
Twitter was soon buzzing.
"Isner vs mahut drawing each other in the first round after last year is the most amazing thing I've seen in tennis! Centre court anyone?!" fourth-seeded Andy Murray said.
Former U.S. Davis Cup captain Patrick McEnroe borrowed his brother John's famous catchphrase as he posted: "you cannot be serious!!!"
The match last year was played on Court 18, and a plaque this year commemorates the epic contest. Isner said he didn't mind which court they played on.
"I don't care what they do," Isner said. "It's going to be crazy, they might put us on a bigger court, (or) put us back on that court (18)."
This year's match is to take place -- or begin at least -- Tuesday. Their first-round match last year was held over twice because of darkness. With rain forecast for the opening week of Wimbledon, there is a chance they could be delayed again.
The top-seeded Nadal will start against Michael Russell of the United States in the opening match on Centre Court Monday.
Nadal could come up against the big-serving Milos Raonic in the third round and then 2009 U.S. Open champion Juan Martin del Potro in the last 16. If the seedings hold, Nadal's quarterfinal could be a rematch of last year's final against Tomas Berdych.
Federer has second-seeded Novak Djokovic as his projected semifinal opponent. The third-seeded Swiss will face Mikhail Kukushkin of Kazakhstan in the first round, and could encounter former finalist David Nalbandian in the third round.
Djokovic meets Jeremy Chardy of France in the first round.
Of the top four, Murray likely has the most difficult route to the final. Before a possible semifinal against Nadal, he could face Marin Cilic in the third round, Richard Gasquet in the last 16 and three-time finalist Andy Roddick in the quarterfinals.
Murray will meet Daniel Gimeno-Traver of Spain in the first round.
The sisters have won nine of the past 11 Wimbledon finals. Serena, who has won four, is 3-1 against five-time champion Venus in the final.
Serena has played only two matches since winning the title last year after complications from a foot injury led to blood clots on her lungs. She returned in Eastbourne this week, losing a three-set match to Vera Zvonareva.
Zvonareva could meet Venus, who is seeded 22nd, in the fourth round at Wimbledon. Venus opens against Akgul Amanmuradova of Uzbekistan while Serena takes on Aravane Rezai of France. Zvonareva plays Alison Riske of the United States.
As the defending champion, Serena's first-round match Tuesday will be on Centre Court.
French Open champion Li Na has a potentially tough second-round match. If she gets past Alla Kudryavtseva of Russia in the first round, she could face Sabine Lisicki. Lisicki won the Birmingham title on grass last week and was awarded a wild card at Wimbledon after a long injury layoff.
Information from The Associated Press was used in this report.