On Tuesday, they both wasted little time in winning opening-round matches at the Hall of Fame Tennis Championships.
Isner, who entered the tournament on a wild-card entry after No. 1 seed and defending champion Mardy Fish withdrew when he was selected for the United States Davis Cup team, needed just 63 minutes to beat Karol Beck, 6-3, 6-2, in a first-round match on center court.
Mahut was even faster, beating Sebastian Decoud, 6-1, 6-0, in just 51 minutes. Mahut played his match on a side court while Isner was also in action.
"It's something we're not used to," Isner said, breaking into a smile. "The points actually aren't grinding like hard court or clay. It's good to go out there and get a real good sweat. Any match that's this quick is good, especially the first round.
"I'm just glad when I picked my opponent at the draw party, I didn't pick him," Isner said. "I would love to play him again — not in a first round."
Isner outlasted Mahut in 11 hours, 5 minutes last year at Wimbledon. Last month, the pair met again, with Isner winning in three sets in a match that lasted about two hours.
"If we play each (here) it's in the final, then we'd both be happy," Mahut said.
When asked if he's glad the questions about their lengthy meeting have started to fade, he smiled and said, "Yes. I think John and I are both happy."
After Fish withdrew, Isner took over the tournament's No. 1 seed by virtue of his No. 46 overall ranking in the world, which is the highest of any competitor in Newport this week.
A No. 1 has never won the title in the 35 years of the tournament.
In other first-round play, wild card Denis Kudla survived 24 aces against him to beat hard-serving Ivo Karlovic, 7-6 (4), 4-6, 6-4; qualifier Jimmy Wang upset third-seeded Igor Kunitsyn, 4-6, 7-5, 6-2; No. 8 seed Tobias Kamke beat Alex Bogdanovic, 7-6 (3), 6-3; Edouard Roger-Vasselin beat qualifier Richard Bloomfield, 6-4, 6-0.