We evaluated the potential effects of a hypothetical vaccine in preventing invasive methicillin-resistant Staphylococcus aureus (MRSA) disease in the United States. Using an active, population-based surveillance program, we estimated baseline disease rates in the United States and compared three distinct vaccination strategies which targeted adults > or =65 years of age, persons at risk for recurrent invasive infection, and patients at hospital discharge. The strategies were projected to reduce the burden of invasive MRSA disease by 12.1%, 13.9% and 17.6%, respectively; with the strategy of vaccinating both adults > or =65 years of age and all adults at hospital discharge having the greatest impact per dose. Our data suggest that availability of an effective S. aureus vaccine could result in substantial reductions in invasive MRSA disease incidence. As candidate vaccines are evaluated, these data will be important in determining the optimal vaccination strategy.