Frequent antihistaminic side effects noted during treatment of depression by tricyclic drugs, as well as the high affinity of tricyclic antidepressants for H₁ receptors in mouse neuroblastoma cells, suggest possibly useful antihistaminic properties. We investigated the antipruritic activity of topically applied 5% solutions of doxepin hydrochloride (Adapin; Sinequan) and amitriptyline hydrochloride (Elavil) and compared such activity to that of a 5% solution of diphenhydramine and vehicle alone. Test solutions were applied to 25-cm² areas on the flexor forearms of forty subjects, and the development of itch to single drops of eight dilutions of histamine phosphate instilled in each area was reported over a 3-minute period. The lowest concentration of histamine able to elicit unequivocal itching in each treated area was the histamine itch threshold (HIT). Doxepin, amitriptyline, and diphenhydramine all produced significantly higher mean and median HITs (p < 0.01) than did vehicle control. Sixty-eight percent of subjects had a HIT ≥2 × 10⁻⁴ mg/ml in doxepin-treated areas versus 58% for amitriptyline, 53% for diphenhydramine, and 25% for vehicle. Our data suggest that tricyclic antidepressants are effective topical antipruritic agents.