Hypoglycemia is a known complication of some antidiabetic drugs (although not incretin-based therapies). The cardiovascular (CV) outcomes of patients experiencing hypoglycemia have not been well studied. We evaluated the consequence of reported hypoglycemia on the risk for subsequent major adverse CV events (MACE; CV death, nonfatal myocardial infarction or nonfatal stroke). Patients in the EXAMINE trial (N=5380) were at elevated risk for MACE due to baseline type 2 diabetes and acute coronary syndrome within the 15-90 days prior to study entry. EXAMINE patients were randomized to double-blind alogliptin or placebo in addition to standard antidiabetic treatment (adjusted throughout the trial). Most patients were men (68%), white or Asian (73%, 20% respectively) and the mean (SD) age was 61 (9.9) years. Metformin, sulfonylureas and insulin were commonly used at baseline (66%, 47% and 30% of patients, respectively). During the trial, 354 (6.6%) patients were reported to have hypoglycemia (6.7% with alogliptin and 6.5% with placebo); rates of serious hypoglycemia were low (0.7% with alogliptin and 0.6% with placebo). Using a Cox proportional hazards model adjusted for baseline covariates (age, sex, HbA1c, antidiabetic treatment) and study treatment, we found a signifi cant increase in MACE among patients who developed serious hypoglycemia (12/34 [35.3%)] vs. those who did not (609/5346 [11.4%)] (adj. HR: 2.42, 95% CI: 1.27-4.60; p=0.007). An increase in MACE was also found for patients with any hypoglycemia (64/354 [18.1%)] vs. those without (557/5026 [11.1%)] (adj. HR: 1.38, 95% CI: 1.05-1.80; p=0.019). Hypoglycemia, in addition to being an adverse event for patients, may have negative CV prognostic implications. Further research on the impact of treatment induced hypoglycemia on CV events is warranted.