OBJECTIVES: The cardiovascular outcomes of oral antidiabetic drugs in type 2 diabetes are still unknown. METHODS: We identified 1,035,824 patients with type 2 who initiated oral antidiabetic drugs in Korea between January 1, 2005, and December 31, 2011, using national claim data, and outcome data were linked with the national registries of hospital admissions and vital statistics. Our study evaluated the cardiovascular effects of metformin as initial pharmacotherapy and different second-line agents added on metformin. The primary outcome was a composite of cardiovascular death, myocardial infarction, or ischemic stroke, and the follow-up was performed through December 31, 2013 RESULTS: Among 423,081 patients who are initiating oral antidiabetic drugs, 208,990 (49.4%) began diabetes treatment with metformin. During 3 years of follow-up, the adjusted risk of primary outcomes was significantly lower in the metformin user than in the metformin non-user (hazard ratio, 0.94; 95% CI, 0.91 to 0.97; P < 0.001). Among 157,509 patients who were requiring second-line agents add-on metformin, 123,830 (78.6%) used sulfonylureas, 9,848 (6.3%) used thiazolidinediones, and 23,831 (15.1%) used dipeptidyl peptidase 4 [DPP-4] inhibitors. Compared with sulfonyurea, the addition of thiazolidinediones or DPP-4 was associated with reduced risks for cardiovascular events (hazard ratio, 0.69; 95% CI, 0.57 to 0.84; P<0.001 and hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001, respectively). CONCLUSIONS: Among patients with type 2 diabetes who were initiating oral diabetes drugs, metformin use was significantly associated with a decreased risk of major adverse cardiovascular events. And, the addition of thiazolidinediones or DPP-4 inhibitors vs sulfonyurea on metformin was associated with a decreased cardiovascular risk.