In a double-blind clinical trial involving 28 patients with multiple sclerosis and major depressive disorder, 14 patients were randomly assigned to a 5-week trial of desipramine and individual psychotherapy and 14 to placebo plus psychotherapy. Clinical judgments indicated that patients treated with desipramine improved significantly more than the placebo group. This was confirmed by scores on the Hamilton Rating Scale for Depression but not by Beck Depression Inventory scores. Side effects limited desipramine dosage in half of the treated patients. The authors conclude that desipramine has a modest beneficial effect in serious depression associated with multiple sclerosis but that side effects may be more of a limiting factor than in patients without medical or neurologic disease.