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Iles was born in 1960 in Stuttgart, Germany, where his physician father ran the U.S. Embassy Medical Clinic. He was raised in Natchez, Mississippi, the setting of many of his novels. After attending Trinity Episcopal Day School, he graduated from the University of Mississippi in 1983.
Iles spent several years as a guitarist, singer, and songwriter in the band Frankly Scarlet. He quit the band after he was married and began working on his first novel, Spandau Phoenix, a thriller about Nazi war criminal Rudolf Hess. Spandau Phoenix was published in 1993.
In 2002, Iles wrote the script 24 Hours from his novel of the same name. Rewritten by director Don Roos, it was renamed Trapped. Iles then rewrote the script during the shoot, at the request of the producers and actors.
In 2011, Iles was nearly killed in a traffic accident on Highway 61 and lost his right leg below the knee. During his three-year recovery, he wrote three volumes of a trilogy set in Natchez, Mississippi, and featuring former prosecutor Penn Cage.
Iles is a member of the literary musical group The Rock Bottom Remainders, which includes authors Dave Barry, Ridley Pearson, Stephen King, Scott Turow, Amy Tan, Mitch Albom, Roy Blount, Jr., Matt Groening, and James McBride. In July 2013, he co-authored Hard Listening (2013) with the group. The ebook combines essays, fiction, musings, email exchanges and conversations, photographs, audio and video clips, and interactive quizzes to give readers a view into the private lives of the authors/musicians.
- Spandau Phoenix (1993) ISBN 0-525-93604-1
- Black Cross (1995) ISBN 0-525-93829-X
- Mortal Fear (1997) ISBN 0-525-93792-7
- The Quiet Game (1999) ISBN 0-525-93793-5
- 24 Hours (2000) ISBN 0-399-14624-5
- Dead Sleep (2001) ISBN 0-399-14735-7
- Sleep No More (2002) ISBN 0-399-14881-7
- The Footprints of God (2003) (also titled Dark Matter) ISBN 0-340-82274-0
- Blood Memory (2005) ISBN 0-7432-3470-7
- Turning Angel (2005) ISBN 0-7432-3471-5
- True Evil (2006) ISBN 0-7432-9249-9
- Third Degree (2007)
- The Devil's Punchbowl (2009) ISBN 978-0-7432-9251-1
- The Death Factory (2014) novella
- Natchez Burning (2014)
- The Bone Tree (2015)
- Unwritten Laws (2017)
- With Rock Bottom Remainders. "Hard Listening" (2013)