Lettieri convincingly projected a remarkable aura of menace and ruthlessness in his film roles, which he attributed to his acquaintance with real-life gangsters, including Joey Gallo. At the age of 36, he made his on screen debut in the made for TV film The Hanged Man. Lettieri played the villain against some of Hollywood's biggest screen names including chasing Steve McQueen in The Getaway, Charles Bronson in Mr. Majestyk, and John Wayne in McQ.
His two most remembered characters, "Sollozzo" from The Godfather and "Rudy" from The Getaway, are lead villains in films in which the "heroes" (main characters) are also villains (bank robbers and the mafia).
Lettieri is the only actor credited as "starring" in The Godfather who is not on the movie poster.
Lettieri died of a heart attack in 1975, at the age of 47, leaving two children. His daughter, Alda Lettieri, is a stage actress in New York City.