In a double-blind, vehicle-controlled study, all of six psoriatic plaques treated with intralesional cyclosporine administered three times weekly for 4 weeks showed complete clearing or incomplete but significant clearing in comparison with vehicle-treated plaques (p less than 0.01). Epidermal thickness decreased from 0.42 +/- 0.07 to 0.27 +/- 0.08 mm at 4 weeks (p less than 0.03). Biopsy specimens obtained on day 5, before any clinical improvement, revealed a significant reduction of epidermal DR+CD1- antigen-presenting cells, epidermal and dermal monocytes, and keratinocyte intercellular adhesion molecule-1 expression. By day 5 the stratum corneum reverted to normal in the plaques receiving cyclosporine. Pain at the injection site was the major side effect. Steady-state blood cyclosporine levels ranged from 20 to 30 ng/ml during the first 12 hours after injection and became undetectable at 48 hours. These data suggest that cyclosporine improves the skin of patients with psoriasis by a local mechanism of action.