Three double-blind, placebo-controlled evaluations of acyclovir were performed in first-episode genital herpes infections. In one trial intravenous acyclovir or saline was administered in hospital over 5 days. In the other two trials, 10-day courses of oral, or 7-day courses of topical acyclovir and respective placebos were followed up in the outpatient department. Regular assessments included staging examinations, culture of lesions and blood and serum analyses. No patient discontinued medication because of an adverse reaction, although one quarter of topically treated patients complained of local irritation on application. The placebo-controlled evaluations indicate that, if given within the first 7 days after the onset of lesions, topical, intravenous and oral acyclovir are useful in shortening the course of first-episode primary genital herpes. The clinical and virological effects of intravenous and oral acyclovir were more marked than those of topical treatment in the reduction of viral shedding; the time to complete healing of lesions; and in the reduction of new lesion formation. Systemic preparations of acyclovir also decreased the symptoms of herpes simplex virus urethritis and intravenous acyclovir those of herpes simplex virus cervicitis. Neither systemic treatment, however, was effective in delaying or reducing the frequency of subsequent recurrences, which may be related to the development of early ganglionic infection. Despite this, acyclovir treatment is a significant advance in the management of primary genital herpes.