BACKGROUND: Upper respiratory tract illnesses have been associated with an increased risk of ischemic heart disease and stroke. During two influenza seasons, we assessed the influence of vaccination against influenza on the risk of hospitalization for heart disease and stroke, hospitalization for pneumonia and influenza, and death from all causes. METHODS: Cohorts of community-dwelling members of three large managed-care organizations who were at least 65 years old were studied during the 1998-1999 and 1999-2000 influenza seasons. Administrative and clinical data were used to evaluate outcomes, with multivariable logistic regression to control for base-line demographic and health characteristics of the subjects. RESULTS: There were 140,055 subjects in the 1998-1999 cohort and 146,328 in the 1999-2000 cohort, of which 55.5 percent and 59.7 percent, respectively, were immunized. At base line, vaccinated subjects were on average sicker, having higher rates of most coexisting conditions, outpatient care, and prior hospitalization for pneumonia than unvaccinated subjects. Unvaccinated subjects, however, were more likely to have been given a prior diagnosis of dementia or stroke. Vaccination against influenza was associated with a reduction in the risk of hospitalization for cardiac disease (reduction of 19 percent during both seasons [P<0.001]), cerebrovascular disease (reduction of 16 percent during the 1998-1999 season [P<0.018] and 23 percent during the 1999-2000 season [P<0.001]), and pneumonia or influenza (reduction of 32 percent during the 1998-1999 season [P<0.001] and 29 percent during the 1999-2000 season [P<0.001]) and a reduction in the risk of death from all causes (reduction of 48 percent during the 1998-1999 season [P<0.001] and 50 percent during the 1999-2000 season [P<0.001]). In analyses according to age, the presence or absence of major medical conditions at base line, and study site, the findings were consistent across all subgroups. CONCLUSIONS: In the elderly, vaccination against influenza is associated with reductions in the risk of hospitalization for heart disease, cerebrovascular disease, and pneumonia or influenza as well as the risk of death from all causes during influenza seasons. These findings highlight the benefits of vaccination and support efforts to increase the rates of vaccination among the elderly.