The guitarist's wife, Swahili Blonde musician Nicole Turley, has filed papers in a Los Angeles court to end their almost four-year marriage.
Turley cites irreconcilable differences for the split and is seeking spousal support and legal fees.
The couple, which wed in 2011, has no kids.
The rocker, 45, has hired celebrity divorce attorney Laura Wasser to represent him in the case, according to TMZ.com.
Frusciante previously enjoyed romances with artist Toni Oswald, supermodel-turned-actress Milla Jovovich and actress Stella Schnabel.