Phelps swore he wouldn't race the demanding event again after he won it at the Beijing Olympics, part of his record eight-gold haul at the 2008 Games.
But the 14-time Olympic gold medallist, who won in 4:12.51, admitted Friday he could change his mind before he finalizes his programme for London.
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"It all depends on if I'm able to swim the other events," he said. "If it's not going to mess up the over events, who knows? Yes, I know that's different than I said before."
Phelps out-dueled fellow American Tyler Clary, taking an early lead on the opening butterfly leg only to have Clary move ahead on the backstroke.
Phelps regained the lead in the breaststroke and held off Clary on the closing freestyle.
Clary's time of 4:13.01 was the fourth-fastest this year.
Phelps said it was the first time he ever swam under 4:13 in the event while in the midst of heavy in-season training.
Coach Bob Bowman said a return to the 400m medley in London was a possibility, but even if that doesn't happen Phelps's performance was encouraging.
"I wouldn't say the door is completely closed. There's probably a crack after tonight," Bowman said.
"But it is a great indication that he's made a lot of progress since January and he's in much better condition."
Hungary's Katinka Hosszu won the women's 400m medley in 4:32.83, second-fastest in the world this year behind Hanna Miley. American Caitlin Leverence was a distant second in 4:36.46.
Missy Franklin won the women's 200m backstroke in 2:07.97, fourth-quickest in the world this year.
Allison Schmitt had denied Franklin in the 200m freestyle, winning in 1:56.79 with Franklin second in 1:57.97.
South Africans Darian Townsend and Jean Basson went one-two in the men's 200m free, Townsend snatching the victory in 1:47.46 to Basson's 1:47.94.
Germany's Yannick Lebherz won the men's 200m backstroke in 1:57.52, edging US teenager Ryan Murphy (1:57.82) in a final that saw Clary and Eugene Godsoe disqualified.
Lebherz's time is the fifth-fastest in the world this year, with Japan's Ryosuke Irie currently atop the Olympic-season world rankings with a time of 1:54.02.
Ryan Lochte -- who scratched from the 200m free final -- was denied a podium finish, settling for fourth in 1:59.34. He had led at every turn before fading in the final 50m.
"I don't know what happened. It happened so fast," Lochte said. "Actually, it happened so slow. I knew I had to go out fast, and if I want to do well, I have to learn how to go out fast and hold on ... I've got two more months (to train)."
Madison Kennedy won the women's 50m free in 24.99, while veteran Dara Torres, her sights set on a sixth Olympic appearance at the age of 44, finished sixth in 25.47.
Jessica Hardy failed to qualify for the championship final, but won the consolation final in a solid 25.04sec.
Nathan Adrian won the men's 50m free, adding the title to the 100m free he captured ahead of Phelps on Thursday.
Adrian edged Trinidad and Tobago's George Bovell 21.88 to 21.89.
