OBJECTIVE: Clomipramine, a serotonin reuptake blocker that has unique antiobsessional properties, was hypothesized to have a different effect from that of desipramine, a tricyclic antidepressant with selective adrenergic effects, for the stereotyped, repetitive behaviors in autism. METHOD: Seven subjects, ages 6-18 years, with autistic disorder completed a 10-week double-blind, crossover trial of clomipramine and desipramine following a 2-week single-blind, placebo phase. RESULTS: Clomipramine was superior to desipramine and placebo, as indicated by standardized ratings of autism and anger as well as ratings of repetitive and compulsive behaviors. Clomipramine and desipramine were equally superior to placebo for ratings of hyperactivity. Parents of all seven subjects elected to have their children continue to take clomipramine after the study. CONCLUSIONS: Clomipramine and desipramine are differentially effective in treating the obsessive-compulsive and core symptoms in autistic disorder. Biological links between compulsions and stereotyped, repetitive behaviors in autistic disorder should be explored.