Forty-three immunocompromised patients with progressive cutaneous herpes simplex virus infections were studied in a double-blind, placebo-controlled evaluation of topically applied acyclovir. Patients were randomized and 22 received acyclovir and 21 placebo; medications were applied four times daily for 10 days. Both study populations were balanced for all demographic characteristics. Acyclovir therapy resulted in no median differences in time to total healing compared with placebo responses, p = 0.13. However, those patients who received the acyclovir ceased shedding virus more rapidly, p < 0.001, and lost pain more readily, p = 0.04, than placebo counterparts. Neither group experienced adverse effects. Because of the protracted nature of mucocutaneous herpes simplex infections in these patients, the immunocompromised host provides a good model for evaluation of topical antiviral therapy. © 1982.