To explore the magnitude and descriptive epidemiology of neonatal herpes simplex virus (HSV) infection, the Centers for Disease Control (CDC) conducted an 18-month hospital-based surveillance study in which 184 cases were reported. Only 22% of mothers had a history of genital HSV infection and only 9% had genital lesions at the time of delivery. Cesarean delivery initiated prior to membrane rupture failed to prevent infection in 15 cases. These data confirm previous observations that most mothers of infected neonates have no history of genital HSV and are asymptomatic at delivery. Furthermore this study suggests that intrauterine infection may be an important route of transmission and underscores the limitations of current prevention strategy.