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Exercise has been shown to improve many health outcomes and well-being of people of all ages. Long-term studies in older adults are needed to confirm disability and survival benefits of exercise.Annual self-administered questionnaires were sent to 538 members of a nationwide running club and 423 healthy controls from northern California who were 50 years and older beginning in 1984. Data included running and exercise frequency, body mass index, and disability assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI; scored from 0 [no difficulty] to 3 [unable to perform]) through 2005. A total of 284 runners and 156 controls completed the 21-year follow-up. Causes of death through 2003 were ascertained using the National Death Index. Multivariate regression techniques compared groups on disability and mortality.At baseline, runners were younger, leaner, and less likely to smoke compared with controls. The mean (SD) HAQ-DI score was higher for controls than for runners at all time points and increased with age in both groups, but to a lesser degree in runners (0.17 [0.34]) than in controls (0.36 [0.55]) (P < .001). Multivariate analyses showed that runners had a significantly lower risk of an HAQ-DI score of 0.5 (hazard ratio, 0.62; 95% confidence interval, 0.46-0.84). At 19 years, 15% of runners had died compared with 34% of controls. After adjustment for covariates, runners demonstrated a survival benefit (hazard ratio, 0.61; 95% confidence interval, 0.45-0.82). Disability and survival curves continued to diverge between groups after the 21-year follow-up as participants approached their ninth decade of life.Vigorous exercise (running) at middle and older ages is associated with reduced disability in later life and a notable survival advantage.