Vidarabine (adenine arabinoside) was evaluated for treatment of neonatal herpes simplex virus infection in a randomized controlled study. Of 56 infected newborns, 13 had infection of skin, eye, or mouth only, 16 had localized brain disease (CNS), and 27 had disseminated disease. Both treatment and placebo groups were comparable by disease distribution and for major population characteristics. Because of the severity of CNS and disseminated disease, these groups were combined for mortality assessment. Mortality was significantly reduced in babies with CNS and disseminated disease from 74% to 38% with drug therapy, P = .014. Outcome in babies with disseminated disease alone, although improved, was poor. Death rate was reduced from 85% to 57% with therapy. Only 14% of drug and 8% of placebo recipients were assessed as normal at 1 year of age. Outcome was better with localized CNS disease; mortality was reduced from 50% to 10%. With treatment, 50% of infected newborns were normal and without only 17%. With skin, eye, or mouth infection death did not occur; however, severe sequelae occurred in 38% of placebo and minor sequelae in 25% of drug recipients. No evidence of acute toxicity was identified in this study. Thus, a beneficial effect of vidarabine therapy on neonatal herpes simplex infection is similar to that evident with therapy of herpes simplex encephalitis occurring in older individuals. Nevertheless, improvement in the mode of therapy or the development of more potent antiviral drugs is essential.