Objective: Olanzapine, an atypical antipsychotic, has been shown to be efficacious for treatment of psychotic and mood disorders in adults. This prospective, open-label study was conducted to examine the safety and usefulness of olanzapine in treating disruptive behavior disorders in adolescents with subaverage intelligence. Method: Sixteen adolescents (ages 13-17 years) with borderline to moderate mental retardation and disruptive behavior were enrolled in an 8-week olanzapine trial (5-20 mg/day). Dependent measures included the Aberrant Behavior Checklist, Conners Parent Rating Scale, Clinical Global Impressions, and two side effects scales. Results: Statistically significant improvement (p less than 0.002) was found on the Irritability and Hyperactivity subscales of the Aberrant Behavior Checklist and the Conners Parent Rating Scale Hyperactivity Index. No subjects developed extrapyramidal side effects. However, four were terminated prematurely from the trial because of either worsening of symptoms (requiring psychiatric inpatient hospitalization in two subjects) or side effects. The most common side effect for the sample was weight gain (averaging 12.7 lb), with 67% of subjects gaining greater than or equal to 10 lb. Although there was also a statistically significant increase in prolactin levels, no subjects reported prolactin-related side effects (e.g., gynecomastia, galactorhea, amenorrhea). Conclusion: Olanzapine may be useful in treating disruptive behavior in adolescents with subaverage intelligence. However, side effects, especially weight gain, are a significant issue. Future double-blind, placebo-controlled studies need to confirm these findings and assess long-term safety and outcome of olanzapine treatment. (Contains 3 tables.)