OBJECTIVES: Universal vaccination against Hepatitis B virus (HBV) is effective to control HBV infection. Hepatitis B immunoglobulin (HBIG) given to neonates helps further reduce HBV transmission. The objectives are 1) to compare the cost-effectiveness of four strategies for HBV screening and HBIG treatment in settings with a universal vaccination policy, and 2) to identify cost-effective HBIG strategies for different HBV prevalence rates.  METHODS: We used Taiwan as an example and developed a decision analysis model to estimate the clinical and economic outcomes of HBV infection for a hypothetical cohort of 100,000 newborns. The four strategies were 1) Strategy V: vaccination only for all neonates, no screening or HBIG treatment,; 2) Strategy S: maternal screening HBsAg, HBIG given for neonates born to HBsAg-positive mothers; 3) Strategy E: maternal screening HBeAg, HBIG given for neonates born to HBeAg-positive mothers; and 4) Strategy S&E: maternal screening HBsAg then HBeAg, HBIG given for neonates born to HBeAg-positive carrier mothers.  RESULTS: In Taiwan, if willing-to-pay (WTP) over $3000 to avert a case of HBV infection, Strategy S would provide the best protection. For WTP between $1500-3000, Strategy E would be preferred at HBV prevalence > 14%, followed by Strategy S&E at prevalence 5-13%, and finally Strategy S at prevalence < 5%. For WTP less than $1,500, Strategy V would be optimal.  CONCLUSIONS: The optimal strategy is a function of WTP and HBV prevalence which usually declines gradually following the launch of immunization. This study provides a roadmap for considering alternative approaches to targeting HBIG treatment after the introduction of HBV vaccine.