The two actors play longtime lovers in "Love Is Strange," a film directed and co-written by Ira Sachs that premiered at the Sundance Film Festival.
Molina, 60, called the pairing "brilliant." Lithgow, 68, said it was "sensational."
"You don't usually put two combustible chemical elements together like that, and that's what's so exciting about this," Lithgow said. "We're brothers in arms when it comes to acting."
Both are veterans of the stage and screen. In "Love Is Strange," they portray a couple who marry after 39 years together. The two are shown in all the intimate settings befitting a longtime pair.
"Somehow, us embracing and cuddling in a bed and kissing each other—it was far more, in a curious way, we were less self-conscious doing that than I would have been playing the part with a woman, perhaps," Lithgow said. "It just has so much to do with the friendship and the ease, for some reason, that we have with each other. And I think with the enormous backlog of work that we've done. We've been acting and acting and acting and acting—both of us—for decades. And usually there's only room in a film or a play for one of us. We're both larger than life character men."
Molina described them as "scenery chewers," adding that working with his good friend "made the job so much more joyful.
"Because when we started working on the film, we were already linked and together and involved," he said. "We had some investment in each other, not just as colleagues, but as friends."
Molina had already begun filming when Lithgow arrived on set. Molina stopped what he was doing and ran to embrace his old friend.
"Our friendship and just the fact that he makes me laugh, it all feeds into the work," he said. "It all makes the work so much more lovely and fun."
Sachs knew Molina and Lithgow were friends, but he couldn't have anticipated their on-screen chemistry.
"You try to set up an environment in which there's a certain kind of performance and you hope that the other actors raise the bar for everyone around them," Sachs said. "And (they) really did."
Sony Pictures Classics announced it will distribute the film in North American, German and Scandinavian theaters.
The two men so enjoyed working together that they joked about a possible romantic future.
"We've decided to leave our two wives and run off and make a life together," Lithgow said.
Added Molina: "When this interview is over, we're going shopping for furniture."
Follow AP Entertainment Writer Sandy Cohen at www.twitter.com/APSandy.