To evaluate the potential economic value of a Staphylococcus aureus vaccine for pre-operative orthopedic surgery patients, we developed an economic computer simulation model. At MRSA colonization rates as low as 1%, a $50 vaccine was cost-effective [<or=$50,000 per quality-adjusted life year (QALY) saved] at vaccine efficacy >or=30%, and a $100 vaccine at vaccine efficacy >or=70%. High MRSA prevalence (>or=25%) could justify a vaccine price as high as $1000. Our results suggest that a S. aureus vaccine for the pre-operative orthopedic population would be very cost-effective over a wide range of MRSA prevalence and vaccine efficacies and costs.