This case report describes two children who developed hyperammonemia together with frank manic behavior during treatment with a combination of valproic acid and risperidone. One child had been maintained on valproic acid for years and risperidone was added. In the second case, valproic acid was introduced to a child who had been treated with risperidone for years. In both cases, discontinuing the valproic acid resulted in normalization of ammonia levels and cessation of the manic behavior. This case report alerts physicians to the importance of obtaining serum ammonia levels in children treated with valproic acid and risperidone who present with manic behavior.