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PURPOSE We wanted to identify risk factors associated with the development of major depressive disorder (MDD) among patients with type 2 diabetes over time. METHODS In a noninterventional study, 338 adult patients with type 2 diabetes and no MDD diagnosis at baseline were assessed 3 times during 18 months (9-month intervals) to ascertain predictors of MDD. We tested a model incorporating personal, behavioral, biologic, and psychosocial variables to identify predictors of MDD. Exploratory analyses tested whether current negative affect mediated the relationship between predictors and subsequent MDD. We also conducted a stratified analysis of moderate vs high negative affect to explore whether level of baseline negative affect mediated the relationship between specific predictors and MDD. RESULTS Prior MDD and negative affect predicted future development of MDD. In subpopulations stratified by moderate negative affect, negative life events, an elevated body mass index (BMI), prior MDD, and poor control of glycated hemoglobin (hemoglobin A1c) each predicted MDD. In subpopulations stratified by elevated negative affect, negative life events and poor control of hemoglobin A1c predicted MDD. Current negative affect partially mediated the relationship between prior MDD and subsequent MDD, as well as the relationship between negative life events and subsequent MDD. CONCLUSIONS Although negative affect at baseline was the primary predictor of subsequent MDD, when stratified by negative affect, negative life events, BMI, and poor control of hemoglobin A1c also predicted MDD. Thus, life stresses and patients’ disease-related concerns are important when understanding what predicts subsequent MDD. Addressing depressive symptoms and broader life context issues expands the scope of a potential intervention to reduce the risk of developing MDD in persons with type 2 diabetes.