OBJECTIVE To analyze the policy of vaccinating human immunodeficiency virus (HIV)-infected young adults against influenza and pneumococcal infections. METHODS Transition state model of clinical immune deterioration of HIV infection, published data, and experts' estimates for the uncertain variables. Outcome measures are the number of influenza and pneumococcal infection hospitalizations and deaths prevented over 10 years and cost-effectiveness ratios. METHODS Hypothetical cohort of HIV-infected 30-year-old patients. RESULTS Although pneumococcal vaccine effectiveness diminishes with advanced HIV disease, the risks of pneumococcal infection rise substantially. Pneumococcal vaccination was therefore found to be a reasonable prevention strategy at all HIV disease stages: few vaccinations are needed to prevent hospitalizations and deaths, and the vaccination strategy is cost-effective. By contrast, influenza incidence is low among young adults, and HIV-related immunodeficiency increases influenza risks only minimally. Because the vaccine is administered yearly, many more vaccinations must be administered and fewer hospitalizations and deaths are prevented than with pneumococcal vaccination. The costs to extend life expectancy are high, and beyond the costs of other prevention strategies for persons with moderate to severe immunodeficiency. CONCLUSIONS Pneumococcal vaccination is a reasonable prevention strategy for HIV-infected patients at all stages of immunodeficiency. Fewer hospitalizations and deaths are prevented by influenza vaccination, making it a far less cost-effective prevention strategy than pneumococcal vaccination.