Objective: To compare the cardiovascular risks associated with second-line anti-diabetic medications by analyzing the national health insurance claim database. Methods: The Korean National Health Insurance (NHI) Service is the single payer which covers all Korean citizens and residents. We identified all patients who used sulphonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, or thiazolidinedione as a second-line oral anti-diabetic medication added to metformin therapy between January 2011 and June 2015 in the NHI database. Cox’s proportional hazard regression models was used to estimate hazard ratio (HR) and its 95% confidence interval for developing a major cardiovascular event (hospitalizations for myocardial infarction, cerebrovascular disease, unstable angina, heart failure, transient cerebral ischemic attacks, or coronary revascularization) according to the types of second-line medications. Age, gender, calendar index year, duration of therapy, comorbidities (hypertension, dyslipidemia, peripheral vascular disease, and microvascular complications), Charlson’s comorbidity index, and concurrent medications were adjusted as potential confounders. Results: A total of 67,262 initiators of a second-line add-on to metformin of either a sulphonylurea (n = 19,367), dipeptidyl peptidase-4 (DPP-4) inhibitor (n = 44,627) or thiazolidinedione (n = 3,268) were identified. After a mean (standard deviation) of 1.3 (0.7) years of follow-up, 295, 581 and 41 major cardiovascular events occurred in sulphonylurea, DPP-4 inhibitor and thiazolidinedione, respectively. In comparison with the sulphonylurea, adjusted HRs were 0.87 (95% CI: 0.79-0.97) for the DPP-4 inhibitor and 0.84 (95% CI: 0.65-1.07) for the thiazolidinedione. There was no significant difference between subclasses of DPP-4 inhibitor: adjusted HR (95% CI) compared with sulfonylurea was 0.80 (0.62-1.00) for gemigliptin, 0.81 (0.71-0.92) for linagliptin, 0.90 (0.74-1.10) for vildagliptin, 0.93 (0.73-1.17) for saxagliptin and 0.95 (0.83-1.10) for sitagliptin. Conclusion: In the analysis of nationwide real-world data, DPP-4 inhibitor plus metformin and thiazolidinedione plus metformin therapies were associated with lower risk of cardiovascular events compared to sulfonylurea plus metformin therapy.