Almost all neonatal herpes simplex virus infections occur as a result of first-episode maternal infection during late pregnancy when delivery occurs before the development of protective maternal antibodies. Screening of pregnant women for the presence of type-specific herpes simplex virus antibodies has therefore been suggested as a means of identifying women vulnerable to herpes simplex virus acquisition and subsequent transmission of herpes simplex virus to their neonates. Couples in whom herpes simplex virus serotype discordance is identified could be counseled regarding sexual behavior modification to avoid maternal herpes simplex virus infection. However, the ramifications of routine screening for herpes simplex virus susceptibility during pregnancy could be profound in terms of costs, prenatal care delivery, and even social duress. The recent US Food and Drug Administration approval of type-specific herpes simplex virus antibody assays for clinical use lends temporal urgency to the need for a critical examination of the relevant data. After we performed such an evaluation and created a decision analysis model to assess the potential cost-effectiveness of herpes simplex virus antibody screening, we concluded that screening for maternal type-specific herpes simplex virus antibodies cannot be recommended to prevent neonatal herpes.