BACKGROUND: Depressive symptoms are associated with mortality. Data regarding moderation of this effect by age and sex are inconsistent, however. We aimed to identify whether age and sex modify the association between depressive symptoms and all-cause and cardiovascular disease (CVD) mortality. METHODS AND RESULTS: The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a prospective cohort of Black and White individuals recruited between 2003 and 2007. Associations between time-varying depressive symptoms (Center for Epidemiologic Studies Depression scale score ≥4 versus <4) and all-cause and CVD mortality were measured using Cox proportional hazard models adjusting for demographic and clinical risk factors. All results were stratified by age or sex and by self-reported health status. Of 29 491 participants, 3253 (11%) had baseline elevated depressive symptoms. Mean age was 65 (9.4) years, with 55.1% of participants female, 41.1% Black, and 46.4% had excellent/very good health. Depressive symptoms were measured at baseline, on average 4.9 (SD, 1.5), then 2.1 (SD, 0.4) years later. Neither age nor sex moderated the association between elevated time-varying depressive symptoms and all-cause or CVD mortality (all-cause: age 45–64 years adjusted hazard ratio [aHR], 1.38; 95% CI, 1.18–1.61 versus age ≥65 years aHR,1.36; 95% CI, 1.23–1.50; P=0.05; CVD: age 45–64 years aHR, 1.17; 95% CI, 0.90–1.53 versus age ≥65 years aHR, 1.26; 95% CI, 1.06–1.50; P=0.54; all-cause: males aHR, 1.46; 95% CI, 1.29–1.64 versus female aHR, 1.34; 95% CI, 1.19–1.50; P=0.35; CVD: male aHR, 1.32; 95% CI, 1.08–1.62 versus female aHR, 1.22; 95% CI, 1.00–1.47; P=0.64). Similar results were observed when stratified by self-reported health status. CONCLUSIONS: Depressive symptoms confer mortality risk regardless of age and sex, including individuals who report excellent/very good health.