OBJECTIVE: Calls for universal antenatal type-specific herpes simplex virus (HSV) screening to prevent neonatal herpes have recently increased and would affect the four million pregnant women and their partners annually in the United States. We undertook this review to assess the appropriateness of such screening, making relevant comparisons to established antenatal human immunodeficiency virus (HIV) and hepatitis B virus (HBV) screening programs. DATA SOURCES: We conducted a full PubMed and bibliographic search for relevant literature in English available from 1966 through February 2006, using the terms "genital herpes," "neonatal herpes," "decision analysis" or "cost-effectiveness analysis," and "herpes and pregnancy" or "antenatal herpes screening." Comparison literature was obtained by replacing "herpes" with "HBV" or "HIV". METHODS OF STUDY SELECTION: We appraised antenatal type-specific HSV screening using well-established criteria for a good screening program, which we articulated as questions. Of 455 articles we selected those that addressed at least one of the questions and were pertinent to the U.S. population. TABULATION, INTEGRATION, AND RESULTS: We found that neonatal HSV is rare and its incidence is imprecisely defined. There is a lack of evidence supporting the effectiveness of interventions to prevent maternal acquisition of new infection in late pregnancy, which accounts for 60-80% of neonatal herpes. The consequences of universal screening are incompletely understood but include the potential for unnecessary cesarean deliveries and medical treatment, maternal psychosocial stress, and discord among partners. The available evidence indicates universal screening is not cost-effective. In contrast, antenatal HIV and HBV screening programs better satisfy accepted criteria for screening. CONCLUSION: On the basis of this appraisal, universal antenatal type-specific HSV screening to prevent neonatal herpes does not adequately satisfy criteria of a good screening program, and we recommend against its adoption. © 2006 The American College of Obstetricians and Gynecologists.