Self-injury is common in mentally retarded persons and often unresponsive to pharmacotherapy. Based on the assumption that this maladaptive behavior may be related to central nervous system serotonergic imbalance or dysfunction, an open trial with a serotonin uptake inhibitor was conducted. Twenty-one severely to profoundly mentally retarded persons with aggression and self-injurious behavior were treated with 20–40 mg of fluoxetine daily. Marked improvement occurred in 13 patients, moderate in 4, mild in 2, and no improvement in 2 patients treated for a minimum of 3 months. Positive changes occurred in the areas of self-injury, agitation, emotional lability, and aggression. Only one patient required discontinuation of the medication because of anorexia and weight loss; all other patients tolerated the drug without any significant side effects. All were concurrently taking other psychotropic medications, and no adverse drug interactions were noted. Future trials will focus on more homogeneous patient samples and on the therapeutic interactions between concurrently administered psychotropic medications. (J Clin Psychopharmacol 1992;12:27–31)