ABSTRACT A significant and sustained reduction in self-injurious behavior (SIB) was observed in a 17-year-old male with severe to profound mental retardation who was treated in an open clinical trial with fluoxetine. The 45-55% reduction in SIB was accompanied by improvement in affective stability, motor capacities, and social activity. No adverse effects or diminishing therapeutic effects were observed during 2 years of treatment at 40 mg daily. Twelve weeks before the start of the fluoxetine trial, this adolescent had been found to be unresponsive to the opiate receptor blocker naltrexone in a double-blind placebo-controlled trial following identical methodology. This case raises the possibility that different patients with SIB may respond preferentially to pharmacological treatments that modify either serotonin or endorphin mechanisms. The findings also suggest that some cases of SIB may represent a type of obsessive-compulsive disorder or body grooming disorder. Additional clinical studies are needed before fluoxetine can be considered for routine use in treating SIB.