To evaluate the short-term efficacy and tolerability of risperidone and methylphenidate for reducing symptoms related to attention-deficit/hyperactivity disorder (ADHD) in children and adolescents with moderate mental retardation. In a 4-week, single-blind, parallel-group trial, 45 subjects with moderate mental retardation and ADHD were randomized to risperidone or methylphenidate and assessed using objective rating scales for efficacy (SNAP [Swanson, Nolan, and Pelham]-IV and Nisonger Child Behavior Rating Form) and side effects (Barkley's Side Effects Rating Scale and Udvalg for Kliniske Undersøgelser). Both groups had reduced ADHD symptoms during the trial. Repeated-measures analysis of variance yielded a significant effect for the interaction between time and group assignment in SNAP-IV Total scores (F = 3.26; p = .05), suggesting a more pronounced effect for risperidone. There was a significant weight reduction in the methylphenidate group and a weight gain in the risperidone group. Our findings suggest that risperidone is associated with greater reductions in ADHD Total score than methylphenidate in children with moderate mental retardation and ADHD. Comorbidity and the side effects profile might be of importance in choosing between the medications, although it is usually prudent to try stimulants before antipsychotics in such children.