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Life satisfaction (LS), a widely used measure of psychological well-being, has been previously linked with cognitive decline, although sex-differences, as well as the interplay of LS and other established correlates of cognitive health – particularly cognitive reserve (CR) – remain unknown. Thus, we explored the sex-specific interaction between LS an CR for cognitive change over 15 years during aging. For this population-based longitudinal cohort study, data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) were used. The sample included 1871 cognitively intact individuals aged 60 years or older, followed up through regular clinical, functional, and psychological assessment for up to 15 years. Life Satisfaction Index was administered at baseline. CR was a latent factor incorporating education, work complexity, social network and leisure activities. Changes in the Mini-Mental State Examination (MMSE) over 15 years indicated cognitive decline. Linear mixed models, adjusted for personality, chronic disease burden, and depressive symptoms examined cognitive trajectories. The interplay of LSI with CR and sex was assessed in stratified analyses. In mutually-adjusted models, higher LSI was associated with slower cognitive decline in women (β*time = 0.30; p < 0.001), but not in men (β*time = 0.10; p = 0.17), whereas higher CR was predictive of slower decline among both sexes. Among women, high LSI was associated with cognitive preservation in both low- (β*time = 0.40, p < 0.01) and high CR substrata (β*time = 0.26, p < 0.001), whereas in men, the null association of LSI with cognitive change remained across CR strata. Among women, promoting life satisfaction could be beneficial to prevent cognitive decline, whereas in men, cognitive reserve enrichment could be more efficacious. Overall, our findings underscored the importance of accounting for sex-specific differences when examining diverse determinants of cognitive health in old age, as potential targets for more personalized intervention among older adults. not applicable.