PURPOSE The magnitude of the risk of severe hypoglycemia associated with sulfonylureas as the initial treatment for type 2 diabetes in the real-world setting is unknown. We assessed the risk of severe hypoglycemia associated with initiating monotherapy with sulfonylurea compared to metformin for the treatment of type 2 diabetes. METHODS Using the UK Clinical Practice Research Datalink and Hospital Episode Statistics linked to the Office for National Statistics, we identified a cohort of patients with type 2 diabetes who initiated sulfonylureas or metformin monotherapy between April 1, 1998 and December 31, 2012, with follow-up until December 31, 2013. Sulfonylurea users were matched one-to-one to metformin users by high-dimensional propensity scores. Hazard ratios (HR) and 95% confidence intervals (CIs) of severe hypoglycemia, defined as requiring hospitalization, were estimated using Cox proportional hazards models comparing sulfonylureas with metformin monotherapy. RESULTS The study cohort consisted of 14,012 initiators of sulfonylureas matched to 14,012 initiators of metformin. The mean treated follow-up time was 1.41 (standard deviation: 1.84) years. Use of sulfonylurea was associated with an elevated incidence of severe hypoglycemia compared to metformin as the initiating monotherapy for type 2 diabetes (incidence rate: 2.4/1000 person-years; 95% CI: 1.90-2.90; HR: 4.53; 95% CI: 2.76-7.45). CONCLUSIONS Sulfonylureas, when prescribed as the initiating monotherapy for the treatment of type 2 diabetes, is associated with a 4.5 fold increase in the risk of severe hypoglycemia. Given the negative consequences of this outcome, clinicians should consider alternative hypoglycemic agents when metformin is not tolerated or contraindicated.