Antibody responses to herpes simplex virus (HSV) types 1 and 2, as determined by enzyme-linked immunoabsorbent assay (ELISA), neutralization, and immunoblot, were assessed in sera from newborns with documented HSV infections. The antibody response of the newborns was defined by disease duration and correlated with disease classification and outcome. Three unique observations were made. First, the quantity of total antibodies at presentation, as determined by ELISA and neutralization, was not predictive of disease classification or outcome. Second, the frequency and intensity of antibody responses to immunologically recognized HSV polypeptides in newborns with central nervous system and disseminated infections were greater than those in newborns with infections localized to the skin, eye, and mouth. Third, the long-term outcome in HSV-infected newborns could be predicted by the quantity of antibodies to the immediate-early infected cell polypeptide ICP 4. These data provide insight into host response to individual polypeptides and their potential value in predicting long-term prognosis. © 1988 by The University of Chicago.