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His first published story was "The Eight-Thirty to Nine Slot" in Fantastic in 1971. During his early period, he also published under a variety of pseudonyms.
His first novel, What Entropy Means to Me (1972), was nominated for the Nebula Award. He achieved his greatest success with the trilogy of Marîd Audran novels set in a 21st century Middle East, with cybernetic implants and modules allowing individuals to change their personalities or bodies. The novels are in fact set in a thinly veiled version of the French Quarter of New Orleans, telling the fictionalized stories of the transvestites and other people Effinger knew in the bars of that city. The three published novels were When Gravity Fails (1987), A Fire in the Sun (1989), and The Exile Kiss (1991). He began a fourth Budayeen novel, Word of Night, but completed only the first two chapters. Those two chapters were reprinted in the anthology Budayeen Nights (2003) which has all of Effinger's short material from the Marîd Audran setting.
His novelette, "Schrödinger's Kitten" (1988), received both the Hugo and the Nebula Award, as well as the Japanese Seiun Award. A collection of stories was published posthumously in 2005 entitled George Alec Effinger Live! From Planet Earth and includes the complete stories Effinger wrote under the pseudonym "O. Niemand" and many of Effinger's best-known stories. Each O. Niemand story is a pastiche in the voice of a different major American writer (Flannery O'Conner, Damon Runyon, Mark Twain, etc.), all set on the asteroid city of Springfield. ("Niemand" is from the German word for "nobody", and the initial O was intended by Effinger as a visual pun for Zero, and possibly also as a reference to the author O. Henry.)
Other stories he wrote were the series of Maureen (Muffy) Birnbaum parodies, which placed a preppy into a variety of science fictional, fantasy, and horror scenarios.
Effinger died in New Orleans, Louisiana.