Background —Ezetimibe, when added to simvastatin, reduces cardiovascular events following acute coronary syndrome (ACS); we explored outcomes stratified by diabetes mellitus (DM). Methods —In IMPROVE-IT, 18,144 patients post ACS with LDL-C 50-125 mg/dL were randomized to ezetimibe/simvastatin-40mg (E/S) or placebo/simvastatin-40mg (P/S). The primary composite endpoint was cardiovascular death, major coronary events, and stroke. DM was a prespecified subgroup. Results —The 4933 (27%) patients with DM were more often older, female, with prior MI and revascularization, and presented more frequently with non-ST segment elevation ACS compared to non-DM (each p interaction =0.02). The largest relative reductions in DM patients were in MI (24%) and ischemic stroke (39%). No differences in safety outcomes by treatment were present regardless of DM. When stratified further by age, patients ≥75 years had a 20% relative reduction in the primary endpoint regardless of DM (P interaction =0.91), while patients interaction =0.011). When stratified by the TIMI risk score for Secondary Prevention, all patients with DM demonstrated benefit with E/S regardless of risk. In contrast, among non-diabetics, patients with a high risk score experienced a significant 18% relative reduction in the composite of cardiovascular death, MI, and ischemic stroke with E/S compared to P/S, whereas non-diabetics at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin (P interaction 0.034). Conclusions —In IMPROVE-IT the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk non-diabetics. Clinical Trial Registration —URL: https://clinicaltrials.gov Unique Identifier: NCT00202878