Normal adults with six or more episodes of genital herpes in the previous year were enrolled in a one-year, multicenter, double-blind trial comparing placebo with 400 mg of acyclovir administered orally twice daily. Patients with episodes during the study were offered 200 mg of acyclovir administered orally five times daily for five days; this allowed comparison of suppressive and episodic treatment. After one year, 227 (44%) of 519 patients receiving suppressive treatment and seven (2%) of 431 receiving placebo (episodic) treatment remained free of recurrences, and the mean numbers of recurrences per year were 1.8 and 11.4, respectively. Among 67 patients who had received suppressive therapy for one year, the mean duration of lesions in the first episode following the discontinuation of treatment was 9.3 days compared with 7.3 days among 45 patients who had received episodic therapy for one year. Treatment was well tolerated, and no changes were noted in the in vitro susceptibility to acyclovir of herpes simplex virus cultured during or after the one-year trial. Continuous or episodic oral acyclovir therapy for one year remained safe and effective.