This was a double-blind, placebo-controlled crossover trial of imipramine (3 mg/kg/day) in 10 profoundly retarded residents. Two groups were formulated: one with depressivelike (or affective) symptoms and one with acting-out behaviors. Measures of drug response included ratings of ward behavior using the Aberrant Behavior Checklist, interval samples of behavior in the living units, and observations of behavior in a playroom situation. Results indicated that the drug caused behavioral deterioration in the Irritability, Lethargy/social withdrawal, and Hyperactivity dimensions of the rating scale, irrespective of subgroup. In addition, gross motor activity was significantly increased on the wards due to imipramine, and it was found that the affective group became less active and the acting-out group more active during free play. Physical side effects were uncommon. These unexpected adverse behavioral effects were discussed with respect to dosage and diagnostic considerations.