Patients with bilateral forebrain disease may commonly manifest the syndrome of pathologic laughing and weeping. We investigated the efficacy of low-dose amitriptyline in 12 patients in whom this syndrome was a consequence of multiple sclerosis. In a double-blind crossover study comparing amitriptyline with placebo, eight patients experienced dramatic and significant improvement with amitriptyline (P = 0.02). The mean dose of amitriptyline was 57.8 mg per day and did not exceed 75 mg per day in any patient. Concurrent measurements of depression showed no change during the study. We conclude that amitriptyline is effective in the treatment of this disturbance of affective expression, and that this effect is distinct from the antidepressant effect of the medication.