Alterations in the cutaneous vascular system are prominent in psoriasis and may play an important role in the pathogenesis of this disorder. We evaluated the effects of topically applied capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a known inhibitor of cutaneous vasodilatation, on moderate and severe psoriasis. Under a double-blind paradigm, forty-four patients with symmetrically distributed psoriatic lesions applied topical capsaicin to one side of their body and identical-appearing vehicle to the other side for 6 weeks. After 3 and 6 weeks of treatment, we performed ratings on changes in scaling and erythema, as well as overall improvement of the psoriasis. Over the course of the study, significantly greater overall improvement was observed on sides treated with capsaicin compared to sides treated with vehicle. Similarly, significantly greater reductions in scaling and erythema accompanied capsaicin application. Burning, stinging, itching, and redness of the skin were noted by nearly half of the patients on initial applications of study medication but diminished or vanished upon continued application. These results suggest that topical application of capsaicin may be a useful new approach in the treatment of psoriasis.