OBJECTIVE To examine the cost-effectiveness of pre- and postexposure approaches for ensuring hepatitis B protection among previously vaccinated healthcare personnel (HCP). METHODS A decision-analytic model was developed for alternative strategies of ensuring hepatitis B protection under assumptions of 68% and 95% long-term protection after a primary vaccination series. Costs and quality-adjusted life years (QALYs) lost from infections were estimated, and incremental cost-effectiveness ratios (ICERs) were calculated relative to a no intervention alternative over 10 years of intervention. Separate analyses were performed for trainees and nontrainees, using the healthcare system perspective. Trainees face higher risk of exposure and likely received primary vaccination as infants. METHODS General healthcare settings. METHODS Trainee and nontrainee HCP. METHODS Preexposure testing for antibody to hepatitis B surface antigen followed by additional vaccination for HCP without protective antibody levels; postexposure evaluation and management for HCP reporting blood or body fluid exposures RESULTS The preexposure strategy prevents more infections and has higher costs than the postexposure strategy or no intervention. For trainees, 10-year preexposure evaluation ICERs are $832,875 and $144,457 per QALY for 95% and 68% long-term vaccine protection, respectively. Trainee 10-year postexposure evaluation ICERs are $1,146,660 and $191,579 per QALY under the 95% and 68% long-term protection assumptions, respectively. For nontrainees, 10-year ICERs are $745,739 and $1,129,286 per QALY for the preexposure and postexposure evaluation strategies, respectively. CONCLUSIONS ICERs may inform decision makers as they decide whether the added cost of the preexposure strategy provides sufficient value in preventing infections.