If the men's 200 metres freestyle at the 2004 Athens Olympics, featuring Phelps, Ian Thorpe and Pieter van den Hoogenband, was prematurely called the race of the century, then this might as well be the match-up of the millennium.
The two Americans will square off not once, but twice, in the 200 and 400m individual medleys, both lung-bursting events that drain every ounce of energy from swimmers but provide for compelling drama.
For swimming fans, the wait is almost over with the 400 individual on Saturday's opening night of finals.
"This is going to be a special race," said Gregg Troy, the head coach of the US men's team. "I can't imagine a better way to promote our sport than a race like this on the first day."
Natalie Coughlin, the captain of the American women's team, said the whole pool deck was excited about watching the pair duke it out over eight laps.
"It's going to be an awesome race," she said. "And it will have a lot of energy that hopefully gives us a lot of momentum going into the next eight days."
Although Phelps won the 400 individual medley at the last two Olympics and would become the first male swimmer to win the same event three times if he's victorious, he finds himself in the rare position as the underdog.
He dropped the gruelling event from his programme after the Beijing Olympics and was beaten by Lochte in the race at the U.S. Olympic Trials but says he has improved since then.
"I feel like my stroke is getting better and things are coming together but I can only control what I do. I can't control what anyone else does," he said.
While the men's 400 individual medley is the undoubted highlight, three other finals, all with compelling storylines of their own, will also feature on the opening night of finals at the London Aquatic Centre.
The women's 400 individual medley could also produce an American winner with Elizabeth Beisel, who trains in Florida with Lochte, setting the fastest time in the world this year, just ahead of China's Zheng Rongrong.
Sun Yang is the favourite to win the men's 400 metres freestyle. If he does, he will become the first Chinese man to win an Olympic swimming gold medal. His main rival is South Korea's Park Tae-hwan, the Beijing champion.
The Netherlands are the overwhelming favourites to win the women's 4x100 freestyle relay after winning the gold medal at the last Olympics and past two world championships.
(Editing by Greg Stutchbury)