Study objective: To determine whether acyclovir administered orally affects the duration and severity of varicella in otherwise normal children. Design: Randomized, placebo-controlled, double-blind trial. Setting: Patients' residence and university hospital clinic. Patients: One hundred five children between 5 and 16 years of age with laboratory-confirmed varicella entered the study. Of the 102 who were included in the final analysis, 50 received acyclovir and 52 received placebo. Interventions: Placebo or acyclovir was given orally four times daily, for 5 to 7 days. The acyclovir dose was adjusted as follows: 5 to 7 years of age, 20 mg/kg; 7 to 12 years, 15 mg/kg; and 12 to 16 years, 10 mg/kg. Measurements and main results: Acyclovir recipients, compared with the placebo group, defervesced sooner (median, 1 day vs 2 days; p=0.001), experienced onset of cutaneous healing sooner, as reflected by a decrease in number of lesions (median, 3 days vs 2 days; p=0.002), and had fewer skin lesions (median, 500 vs 336; p=0.02). Acyclovir did not significantly change the rate of complications of varicella (10% in the acyclovir group vs 13.5% among placebo subjects). Adverse drug effects were not observed. Acyclovir recipients had lower geometric mean serum antibody titers to varicella-zoster virus than their placebo counterparts 4 weeks after the onset of illness, but antibody titers in both groups were similar 1 year later. Conclusions: These results provide evidence that acyclovir is useful and well tolerated for treatment of varicella in otherwise healthy children.