Sixty-three immunocompromised patients with infections caused by herpes simplex virus were evaluated in a double-blind, placebo-controlled study of topical acyclovir therapy; 33 patients received acyclovir and 30 received the placebo. The two populations of patients were balanced in terms of age, race, sex, underlying disease, preceding chemotherapy, and site, size, and duration of lesions. Acyclovir recipients experienced an acceleration in the clearance of virus (P = .0006), the resolution of pain (P = .004), and the total healing of lesions (P = .038); median temporal differences between populations averaged six days for each of these three parameters. The surface area of herpetic lesions continued to enlarge in placebo recipients after entry into the trial; in contrast, lesion surface area decreased progressively during therapy in drug recipients. The speed of healing was influenced by lesion size. Patients with lesions of ≥ 50 mm2 benefited most from therapy, particularly in terms of pain resolution and time to total healing (median differences between groups, eight days). Irrespective of underlying disease, sex, preceding chemotherapy, or age, acyclovir therapy was of clinical benefit. No adverse clinical or laboratory reactions were encountered.