Sulphonylureas (SUs) subclasses have different risks of all-cause mortality, acute myocardial infarction (AMI), and stroke. Therefore, we assessed these risks in patients with type 2 diabetes mellitus administered gliclazide, glimepiride, or metformin monotherapy with retrospective cohort study design. Total 195,235 subjects were included in the study who were ≥20 years' old and prescribed monotherapy for at least 1 year as a first-line therapy for incident diabetes from January 01, 2009 to December 31, 2013 in the National Health Insurance Service Claim data. Incidence and hazard ratios (HRs) of all-cause mortality, AMI, and stroke were compared with glimepiride monotherapy as a reference. Gliclazide monotherapy increased all-cause mortality compared with glimepiride monotherapy. However, the gliclazide and glimepiride groups showed no difference in AMI and stroke incidences. In line with previous studies, metformin monotherapy showed significant clinical benefits in reducing risks of all-cause mortality, AMI, and stroke compared with glimepiride. This population-based cohort study suggested that gliclazide increases risks of all-cause mortality and has similar risk of AMI and stroke with gliclazide monotherapy in Korean.