The 73-year-old singer and guitarist reunited with Chris Frantz, Jerry Harrison and Tina Weymouth two years ago to promote the re-release of their concert film Stop Making Sense.
Before that, the group last performed together when they were inducted into the Rock and Roll Hall of Fame in 2002.
But asked about the possibility of another tour, the Psycho Killer hitmaker has admitted it's unlikely.
"I recall we were on TV together and people went, 'well, they all seem to be getting along'," Byrne told Sunday Times Culture magazine.
"But no, I don't think so. On a practical level, trying to recreate the feeling that people had when they were in their early twenties? The time that they first heard that music? That's a fool's errand.
"And besides, I'm really enjoying what I'm doing."
Byrne's new solo album, Who Is the Sky? is his first in seven years and he deliberately tried to avoid writing about his advancing years.
"Well, I'm certainly aware I am older. "But I have consciously tried not to write about ageing or death approaching," he said.
"It creeps in, but that is a well-trodden subject by songwriters."
Byrne believes he has changed over the years and is a lot more "socially comfortable" than he used to be, crediting the "cathartic" nature of music.
"I have friends who've told me, 'David, some things that you did were ridiculous'," he said.
"I'd invite people over to my house and then go and hide. I don't do that any more."
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