Chickenpox, the primary infection caused by the Varicella Zoster virus, affects more than 3 million children a year in the United States. Although usually self-limited, chickenpox can cause prolonged discomfort and is associated with infrequent but serious complications. To evaluate the effectiveness of acyclovir for the treatment of chickenpox, we conducted a multi-center, double-blind, placebo-controlled study involving 815 healthy children 2 to 12 years old who contracted chickenpox. Treatment with acyclovir was begun within the first 24 hours of rash and was administered orally in a dose of 20 mg per kilogram of body weight four times daily for five days. The children treated with acyclovir had fewer varicella lesions than those given placebo (mean number, 294 vs. 347; P<0.001), and a smaller proportion of them had more than 500 lesions (21 percent, as compared with 38 percent with placebo; P<0.001). In over 95 percent of the recipients of acyclovir no new lesions formed after day 3, whereas new lesions were forming in 20 percent of the placebo recipients on day 6 or later. The recipients of acyclovir also had accelerated progression to the crusted and healed stages, less itching, and fewer residual lesions after 28 days. In the children treated with acyclovir the duration of fever and constitutional symptoms was limited to three to four days, whereas in 20 percent of the children given placebo illness lasted more than four days. There was no significant difference between groups in the distribution of 11 disease complications (10 bacterial skin infections and 1 case of transient cerebellar ataxia). Acyclovir was well tolerated, and there was no significant difference between groups in the titers of antibodies against Varicella Zoster virus. Acyclovir is a safe treatment that reduces the duration and severity of chickenpox in normal children when therapy is initiated during the first 24 hours of rash. Whether treatment with acyclovir can reduce the rare, serious complications of chickenpox remains uncertain. (N Engl J Med 1991;325:1539–44.) © 1991, Massachusetts Medical Society. All rights reserved.