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To evaluate the interaction effects between retinopathy and depression on mortality risks in genral population and subpopulation with diabetes. Prospective analyses were conducted on data from the National Health and Nutrition Examination Surveys study. Associations of retinopathy, depression and their interaction with all-cause, cardiovascular disease (CVD)-specific, cancer-specific and other-specific mortality risk were estimated using Kaplan-Meier curves and multivariate Cox proportional hazards models. Among 5367 participants, the weighted prevalence of retinopathy and depression was 9.6 % and 7.1 %, respectively. After a follow-up period of 12.1 years, 1295 deaths (17.3 %) occurred. Retinopathy was associated with an increased risk of all-cause (hazard ratio [HR]; 95 % confidence interval [CI]) (1.47; 1.27–1.71), CVD-specific (1.87; 1.45–2.41), and other-specific (1.43; 1.14–1.79) mortality. Similar relationship was observed between depression and all-cause mortality (1.24; 1.02–1.52). Retinopathy and depression had a positive multiplicative and additive interaction effect on all-cause (P interaction = 0.015; relative excess risk of interaction [RERI] 1.30; 95 % CI 0.15–2.45) and CVD-specific mortality (P interaction = 0.042; RERI 2.65; 95 % CI −0.12–5.42). Concomitant retinopathy and depression was more markedly associated with all-cause (2.86; 1.91–4.28), CVD-specific (4.70; 2.57–8.62), and other-specific mortality risks (2.18; 1.14–4.15) compared to those without retinopathy and depression. These associations were more pronounced in the diabetic participants. The co-occurrence of retinopathy and depression increases the risk of all-cause and CVD-specific mortality among middle-aged and older adults in the United States, especially in population with diabetes. Focus on diabetic patients and active evaluation and intervention of retinopathy with depression may improve their quality of life and mortality outcomes. • Retinopathy and depression are independent risk factors for mortality. • Retinopathy combined depression dramatically increases mortality risks. • This positive interaction effect is more pronounced in the diabetic participants. [ABSTRACT FROM AUTHOR]