Neutralizing antibody titers to herpes simplex virus type 1 (HSV-1) and HSV-2 were measured at birth in normal infants and uninfected infants of mothers with genital HSV infections during pregnancy and at the onset of infection in 5 infants with mild infections and 11 infants with severe infections. Thirty-eight percent of premature and 29% of term infants had neutralization titers of <1:5. High titers ([unk]1:40) were found in 55% of infants of mothers with primary infections during pregnancy and in 76% of infants of mothers with recurrent infections. The mean titers to HSV-1 and -2 in 5 infected infants with mild infections were 1:56 and 1:65 at the time of onset of infection, whereas the mean titers in 11 infants with severe infections were 1:11 and 1:12. Six natally exposed infants who remained asymptomatic were also studied and had a mean titer to HSV-1 of 1:85 and to HSV-2 of 1:69. Therefore, infants with high titers of transplacentally derived antibody had a more favorable outcome than infants with lower titers. Ninety-five percent of the infants of mothers with recurrent infections had a Rawls index of more than 85, suggesting that the antibody response was to HSV-2. However, low levels of antibody with this type specificity failed to protect four infants from infection with HSV-2. Augmentation of the neutralization titer to HSV-2 by the amount of complement present in cord serum was less than twofold. The study suggests that the quantity of antibody derived transplacentally affects the outcome of infection after natal exposure to herpes simplex virus. Complete neutralization of virus by antibody may occur in some infants, and prolongation of the incubation period and modification of the infection may occur in others.