BACKGROUND: Depression and social isolation are significant public health issues worldwide, characterized by a bidirectional relationship between the two. This study aims to evaluate the combined effects of depression and social isolation on cardiovascular disease (CVD) and mortality, as well as to assess the mediating role of cardiometabolic diseases in these associations. METHODS: This nationwide prospective cohort study utilized data from the China Health and Retirement Longitudinal Study. Depression was assessed using the 10-item Center for Epidemiologic Studies Depression Scale, while social isolation was measured using 4 dichotomized indicators. The outcomes were CVD and all-cause mortality. Logistic regression models and mediation analyses were conducted, and population attributable fractions (PAFs) were calculated. RESULTS: 8567 participants were included in the study, with a mean age of 59.2 (±10.0) years and 48.7 % being men. Among the participants, 5773 (67.4 %) reported neither depression nor social isolation, 1143 (13.3 %) had depression only, 1190 (13.9 %) experienced social isolation only, and 461 (5.4 %) had both depression and social isolation. Individuals with both conditions exhibited the highest odds of CVD (odds ratio (OR): 1.61
95 % confidence interval (CI): 1.27, 2.04) and mortality (OR: 1.61
95 % CI: 1.22, 2.12) (p for trend across groups <
0.001). The estimated PAFs indicated that a significant number of CVD and mortality events could potentially be prevented by addressing depression and social isolation. Mediator analyses revealed significant indirect effects of hypertension and suboptimal BMI on the relationships between depression, social isolation, and the incidence of CVD and mortality. LIMITATIONS: Depression, social isolation, and outcomes were self-reported. CONCLUSION: A significant combined effect of depression and social isolation on CVD and all-cause mortality was observed among middle-aged and older Chinese adults, underscoring the importance of preventing and managing depression and social isolation to alleviate the burden of CVD.