ObjectivesTo assess the association between cognitive reserve (CR) and quality of life (QoL), as well as the role of depression, cognitive functioning, and disability in this association. MethodsNationally-representative cross-sectional population-based data on 1973 individuals aged ≥50years from the Spanish sample of the Collaborative Research on Ageing in Europe (COURAGE) study were analysed. CR was a composite score ranging from 0 to 25 obtained from the Cognitive Reserve Questionnaire, which is composed of items on training courses, occupation, musical training, languages, reading activities, intellectual games, and level of education of the participants and their parents. QoL, ranging from 0 to 100, was assessed with the WHOQOL-AGE. Multiple linear regression and mediation analyses were performed. ResultsHigher levels of CR were associated with higher QoL, after controlling for potential confounders (Coef. 0.53; 95% CI=0.36, 0.70). The strongest mediator in this association was disability, which explained about half of the association, while depression and cognition explained 6–10% of this association. DiscussionCR is associated with higher QoL in older adults. Interventions targeting determinants of CR that can be modified or trained across the lifespan may lead to successful ageing by prolonging autonomous functioning and enhancing QoL.