OBJECTIVE To determine whether oral acyclovir reduces the incidence of recurrent herpes labialis in otherwise healthy patients with proven frequently recurrent disease. METHODS Randomized, double-blind, placebo-controlled, crossover trial. METHODS Outpatient facility of the Clinical Center, National Institutes of Health, Bethesda, Maryland. METHODS Fifty-six otherwise healthy adults who reported frequently recurrent herpes labialis (> or = 6 episodes/y) were enrolled into the study. During a 4-month observation period, 22 patients had herpes labialis two or more times and were eligible for study treatment. METHODS Twenty-two patients were randomized to receive either acyclovir, 400 mg twice daily, or matched placebo for 4 months. After the first treatment period, patients were given the alternate treatment for another 4 months and were then taken off study medication to observe the first post-treatment recurrence. Recurrent outbreaks were determined by examination and by viral culture. RESULTS Twenty patients completed blind treatment with both acyclovir and placebo. The median time to first clinically documented recurrence was 46 days for placebo courses and 118 days for acyclovir courses (P = 0.05). The mean number of recurrences per 4-month treatment period was 1.80 episodes per patient during placebo treatment and 0.85 episodes per patient during acyclovir treatment (P = 0.009). The mean number of virologically confirmed recurrences per patient was 1.40 with placebo therapy compared with 0.40 with acyclovir (P = 0.003). CONCLUSIONS Oral acyclovir, 400 mg twice daily, is effective in suppressing herpes labialis in immunocompetent adults confirmed to have frequently recurrent infection. Treatment with acyclovir in this study resulted in a 53% reduction in the number of clinical recurrences and a 71% reduction in virus culture-positive recurrences compared with placebo therapy.