OBJECTIVE - To investigate major depressive disorder (MDD), which complicates the course of type 2 diabetes and is associated with an increased risk of cardiovascular disease and death. This risk may be due to a greater susceptibility for myocardial infarction (MI) in depressed patients with type 2 diabetes compared with nondepressed patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - Veterans Administration electronic medical records were analyzed to identify a cohort free of cardiovascular disease in fiscal years 1999 and 2000, aged 25 to 80 years. ICD-9-CM codes were used to create a four-level risk group indicating 1) neither diabetes nor MDD (n = 214,749), 2) MDD alone (n = 77,568), 3) type 2 diabetes alone (n = 40,953), and 4) comorbid MDD and type 2 diabetes (n = 12,679). Age-adjusted Cox proportional hazards models were computed before and after adjusting for baseline sociodemographic and time-dependent covariates. RESULTS - After adjusting for covariates, patients with type 2 diabetes alone and patients with MDD alone were at ∼30% increased risk for MI, and patients with type 2 diabetes and MDD were at 82% increased risk for MI (hazard ratio 1.82 [95% CI 1.69-1.97]) compared with patients without either condition. CONCLUSIONS - Compared with patients with only diabetes or only MDD, individuals with type 2 diabetes and MDD are at increased risk for new-onset MI. Monitoring cardiovascular health in depressed patients with type 2 diabetes may reduce the risk of MI in this especially high-risk group.