Background: Vaccination rates for healthy senior citizens are lower than those for senior citizens with underlying medical conditions such as chronic heart or lung disease. Uncertainty about the benefits of influenza vaccination for healthy senior citizens may contribute to lower rates of utilization in this group. Objective: To clarify the benefits of influenza vaccination among low-risk senior citizens while concurrently assessing the benefits for intermediate- and high-risk senior citizens. Methods: All elderly members of a large health maintenance organization were included in each of 6 consecutive study cohorts. Subjects were grouped according to risk status: high risk (having heart or lung disease), intermediate risk (having diabetes, renal disease, stroke and/or dementia, or rheumatologic disease), and low risk. Outcomes were compared between vaccinated and unvaccinated subjects after controlling for baseline demographic and health characteristics. Results: There were more than 20 000 subjects in each of the 6 cohorts who provided 147 551 person-periods of observation. The pooled vaccination rate was 60%. There were 101 619 person-periods of observation for low-risk subjects, 15 482 for intermediate-risk, and 30 450 for high- risk subjects. Vaccination over the 6 seasons was associated with an overall reduction of 39% for pneumonia hospitalizations (P<.001), a 32% decrease in hospitalizations for all respiratory conditions (P<.001), and a 27% decrease in hospitalizations for congestive heart failure (P<.001). Immunization was also associated with a 50% reduction in all-cause mortality (P<.001). Within the risk subgroups, vaccine effectiveness was 29%, 32%, and 49% for high-, intermediate-, and low-risk senior citizens for reducing hospitalizations for pneumonia and influenza (for high and low risk, P≤.002; for intermediate risk, P =. 11). Effectiveness was 19%, 39%, and 33% (for each, P≤.008), respectively, for reducing hospitalizations for all respiratory conditions and 49%, 64%, and 55% for reducing deaths from all causes (for each, P<.001). Vaccination was also associated with direct medical care cost savings of $73 per individual vaccinated for all subjects combined (P = .002). Estimates of cost savings within each risk group suggest that vaccination would be cost saving for each subgroup (range of cost savings of $171 per individual vaccinated for high risk to $7 for low risk), although within the subgroups these findings did not reach statistical significance (for each, P≤.05). Conclusions: This study confirms that healthy senior citizens as well as senior citizens with underlying medical conditions are at risk for the serious complications of influenza and benefit from vaccination. All individuals 65 years or older should be immunized with this vaccine.