OBJECTIVES: The use of combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant and postpartum women provides personal protection and may reduce the risk of transmission of pertussis to their young infants. The study seeks to assess the economic benefits associated with a hospital-based postpartum Tdap vaccination strategy. METHODS: A decision tree model was constructed to calculate the potential cost-benefit of this strategy from a health care system or societal perspective. Probabilities and costs were derived from published literature, Centers for Disease Control and Prevention data, and expert recommendations. The maternal vaccination protection period for infants was defined as 7 months, as the infants do not receive a full series of pertussis immunization before 6 months of age, with 1 month added for maximal development of immunity. 10-year vaccine protection for birth mothers was estimated in the model. All cost estimates were inflated to year 2010 US dollars and discounted at a 3% annual discount rate. RESULTS: From a societal perspective, the average costs per vaccinated and unvaccinated mother were estimated at $132.92 and $232.75, respectively. Our model suggests an expected net benefit (ENB) of $99.83 per postpartum vaccinated mother. The overall societal benefits in the cohort of U.S. birth mothers ranged from $89.8 ~ $287.5 million, depending on the vaccine coverage rate. If including direct medical costs only, the ENB was estimated at -$27.26 per vaccinated mother, suggesting that this strategy is not cost-saving from a health care system perspective. Annual incidence in birth mothers and Tdap efficacy exhibited substantial impact on the model from one-way and two-way sensitivity analyses. CONCLUSIONS: Postpartum Tdap vaccination is likely to generate net benefits in the base case from a societal perspective, if the annual incidence of pertussis among birth mothers exceeds 140 cases per 100,000.