Nineteen mentally retarded inpatients with epilepsy and a history of current or recent aggressive behavior were treated with 20 mg of fluoxetine daily. All were concurrently taking other psychotropic medications, including carbamazepine and neuroleptics. A standardized rating scale (MOAS) was used to assess the effects of fluoxetine on aggressive behavior. There were wide individual differences in drug response. In nine patients, fluoxetine treatment was associated with increased aggression, while drug withdrawal led to a decrease to below pretreatment levels. Two hypotheses concerning the apparent association between fluoxetine and increased aggression are discussed: 1) adverse effects secondary to either drug interaction or fluoxetine overmedication; and 2) a specific serotonergically mediated effect on the regulation of aggression. This study suggests that the clinician who treats mentally retarded patients with impulsive aggressive behavior should remain aware that fluoxetine may have diverse effects on aggression that vary over time and interindividually.