Of 786 children and adolescents enrolled in a multicenter trial of acyclovir for chickenpox, 27 (3.4%) met the case definition of varicella-zoster virus (VZV) hepatitis (serum aspartate aminotransferase level > or = 100 U/l). The clinical and cutaneous manifestations of chickenpox in the 15 placebo recipients with this complication did not differ significantly from those in 45 matched controls (p > 0.05), indicating that liver involvement by VZV is not a consequence of more extensive disease. Although acyclovir modified the course of chickenpox overall, it did not prevent VZV hepatitis; that is, the proportions of affected subjects with liver involvement postenrollment did not differ significantly between the drug and placebo recipients (50% vs 80%, p > 0.05). Serum aspartate aminotransferase levels that were elevated on day 4 postenrollment had returned to normal (< or = 60 U/l) by day 28 in 88% of the placebo group and in 83% of the drug-treated group. With 2 exceptions, all values were normal by 88 days postenrollment. We conclude that chemically defined VZV hepatitis is an infrequent, self-limiting complication of chickenpox in otherwise healthy children and adolescents.