This report is a randomized, double-blind, comparative trial of desipramine with the psychomotor stimulant methylphenidate. Twenty HIV antibody-positive patients with depressive symptoms were randomly assigned to either drug. After individual dose titration, the mean daily dose of desipramine was 150 mg. and methylphenidate 30 mg. daily. The differences in responses between desipramine and methylphenidate were not statistically significant on various measures of depression. The antidepressant effect of methylphenidate did not occur any faster than that of desipramine. Both significantly reduced depressive and anxious symptomatology over the blinded portion of the treatments. Thus, methylphenidate relieves depressive symptomatology with efficacy similar to that of desipramine, offering an alternative to patients who are unable to tolerate standard tricyclic antidepressant therapy. The dopaminergic effects of methylphenidate are likely to mediate its antidepressant effects.