Graffeo said in a statement that his growing career as a guest conductor made it impossible for him to spend enough time.
"I'm delighted to have these artistic opportunities and feel it would be a mistake turn down or cancel them, as I have had to do in the past, owing to my responsibilities at Knoxville Opera," he said.
In addition, Graffeo said that he wanted to spend more time with his family. He and his wife recently had their first child.
During Graffeo's tenure at Knoxville Opera, he oversaw the creation of the Knoxville Opera Rossini Festival, which recently won a "Bravo Excellence" Award from Opera America, and the company's first original production since the 1980s.
Before coming to Knoxville, Graffeo was artistic director of Eugene Opera and head of the opera program at the University of Oregon
Knoxville Opera has launched a search for his successor.