In the scene in the jazz club where Lee Barrett is introduced, the waitress that tells him he has a phone call is played by Lee Remick in an uncredited cameo role.

Anne Francis replaced Joan Hackett.

In his memoirs, Charlton Heston says he was asked to play the lead. In The Omega Man (1971) he does play a doctor who develops a vaccine for a bug that kills most of the population of earth.

Though it follows the general plot rather closely, there are a number of differences between this adaptation and the original novel by Alistair MacLean. Notably among them, in the novel the action is set in the UK, Station Three is called the Mordon Microbiological Research Establishment, George Maharis' character is called Pierre Cavell and Anne Francis' character is called Mary and is actually married to George Maharis' character.

William A. Wellman was offered Gen. Williams.

The following people at one time or another worked with George Maharis on Route 66: Anne Francis, Edward Asner, Simon Oakland, Harold Gould, Frank Sutton, and Henry Beckman.