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Introduction: The association between cognitive reserve (CR) and survival with independence is unknown. We examined whether lifelong CR accumulation is associated with disability-free survival and explored the extent to which cognitive function mediates this association. Methods: Within the Rush Memory and Aging Project, 1633 dementia- and disability-free participants were followed annually for up to 22 years. Lifelong CR including education, early-/mid-/late-life cognitive activities, and late-life social activity was assessed and tertiled. Results: CR score was dose-dependently associated with disability/death (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.93–0.99). Compared to low CR, the HR (95% CI) of disability/death was 0.82 (0.70–0.95) for high CR. The median disability-free survival time was prolonged by 0.99 (95% CI 0.28–1.71) years for participants with high CR. Cognitive function mediated 35.7% of the association between CR and disability-free survival. Discussion: High lifelong CR was associated with prolonged disability-free survival. Cognitive function mediates about one-third of this association. Our findings underscore the importance of CR for healthy aging.