Perinatal transmission of hepatitis B virus is associated with substantial morbidity and mortality, yet controversy still exists regarding the value of routine screening of pregnant women in the United States and subsequent immunization of their at-risk neonates. To evaluate the cost-effectiveness of such a screening and immunization program, we developed a decision analysis model and obtained data from published reports, chart review, and a Delphi survey to determine outcome probabilities and costs. When considering direct and indirect costs, routine screening and immunization would be cost-effective at a prevalence of 0.06%, significantly lower than the national prevalence of 0.2%. At an annual national birth rate of 3.5 million births, a national policy of routine screening of all pregnant women would result in an annual net savings of more than $105 million. In the high-risk groups, as many as 140 cases of acute neonatal hepatitis and as many as 1400 cases of chronic liver disease would be prevented yearly per 100,000 pregnant women screened, at a net annual savings of as much as $765 million.