Estimating the potential health benefits and expenditures of a partially effective HIV vaccine is an important consideration in the debate about whether HIV vaccine research should continue. We developed an epidemic model to estimate HIV prevalence, new infections, and the cost-effectiveness of vaccination strategies in the U.S. Vaccines with modest efficacy could prevent 300,000-700,000 HIV infections and save $30 billion in healthcare expenditures over 20 years. Targeted vaccination of high-risk individuals is economically efficient, but difficulty in reaching these groups may mitigate these benefits. Universal vaccination is cost-effective for vaccines with 50% efficacy and price similar to other infectious disease vaccines.