OBJECTIVE: This study examined health and behavioral risk factors for infections that required hospitalization in postmenopausal women who were enrollees of a large health maintenance organization (HMO). METHODS: Participants were 1365 generally healthy women aged 55 to 80 years who were followed for up to 6 years. Infection diagnoses listed first in the automated hospital discharge records were used to identify hospitalizations for which infections were the primary cause of admission. Potential risk factors for these serious infections were identified from baseline questionnaire information and automated HMO records from before baseline and during follow‐up. Risks for infections associated with hospital admission were examined using multivariate logistic regression methods. RESULTS: Seventy‐three women had a total of 90 hospital admissions in which infection was the primary discharge diagnosis. Behaviors that were independent predictors of infection were physical inactivity (adj. odds ratio = 4.08; 95% CI, 1.73–9.63) and smoking (adj. odds ratio = 2.64; 95% CI, 1.11–6.26). Incident cancer and lung disease were also associated with increased risk of infection. These associations were independent of age, body mass index, functional status, and other measures of health. CONCLUSIONS: Modifiable risk factors such as physical inactivity and smoking may place older women at risk for serious infections although the causal link is yet to be explained. Further research in this area may lead to new strategies aimed at reducing the serious burden of infections in the older population.