Clinical trials suggested that the benefits of ezetimibe-statin combination therapy on major adverse cardiovascular events (MACE) might be greater in patients with diabetes. We aimed to investigate the differential association of ezetimibe-statin combination with incident MACE by presence of diabetes. In this retrospective cohort study, subjects treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) between 2005 and 2015 were 1:1 matched using propensity score as stratified by diabetes. Primary outcome was newly-developed MACE composed of cardiovascular death, ACS, coronary revascularization, or non-hemorrhagic stroke. During 5,077 and 12,439 person-years, the incidence rates of MACE were 24.9, 20.1, 35.3, and 22.8/1000 person-years among no diabetes S, no diabetes S + E, diabetes S, and diabetes S + E, respectively. Relative to no diabetes S, adjusted HR (aHR) for MACE in diabetes S was 1.23 (p = 0.086), whereas S + E was associated with a lower risk of MACE in both non-diabetic patients (aHR 0.76, p = 0.047) and diabetic patients (aHR 0.60, p = 0.007) with significant difference (relative excess risk due to interaction = -0.39, p = 0.044). In conclusion, reduction of MACE risk associated with ezetimibe plus simvastatin therapy relative to simvastatin alone was greater in patients with diabetes than in patients without diabetes.