The controlled evaluation of vidarabine as therapy of neonatal herpes simplex virus (HSV) infection provided an opportunity to collect data to further assess the natural history of maternal and newborn infections. Women delivering infected babies were young, nulliparous, and infrequent aborters. Nearly 50% of the gestations ended in premature labor. Maternal infection was asymptomatic in 39 of 56 (70%) of the mothers, at the time of delivery. However, risk factors included a past history of genital herpes at any time and exposure to a sexual partner with presumed HSV lesions. Associated diseases in children born to these women were common. Premature infants had an incidence of respiratory distress of 52% (14 of 27). Eight of 29 (28%) term newborns had a bacterial infection, antedating the onset of neonatal HSV infection. Virologic studies on infected newborns confirmed that skin lesions were the most frequent site for virus retrieval. Progression of disease from isolated skin lesions was common, occurring in 70% of babies whose presenting sign was skin vesicles. CSF was virus-positive from 14 babies and more frequently in those with localized CNS disease. Importantly, brain biopsy was necessary for diagnosis in four cases. Finally, neither the presence or absence of antibodies to HSV was useful in predicting either presentation or outcome of infection. These studies further emphasize the complex nature of HSV infections of the newborn and need for tertiary care.