Pneumococcal polysaccharide vaccination (PPV) to prevent invasive pneumococcal disease (IPD) is recommended at age 65 for most persons in the US. We used a Markov model to examine alternative PPV strategies, finding that vaccination at ages 50 and 65 prevented more IPD than present vaccination policies; four decennial vaccinations were most effective. The present vaccination policy costs $3341/QALY gained, vaccinations at 50/65 cost $23,120/QALY and four vaccinations (50/60/70/80) cost $54,451/QALY; results were sensitive to vaccine uptake assumptions, with current policy no longer favored at present vaccination rates. PPV at ages 50/65 may be clinically and, depending on cost-effectiveness criterion used, economically favored over present vaccination recommendations.