Objective This study was conducted to evaluate the impact of diabetes on patients with unprotected left main coronary artery (LMCA) disease treated with either percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG). Background The optimal coronary revascularization strategy in diabetic patients with unprotected LMCA disease remains uncertain. Methods A total of 823 consecutive patients having unprotected LMCA disease, who received drug-eluting stent (DES) (n = 331) implantation or underwent CABG (n = 492), were retrospectively analyzed. We compared the effects of these two treatments on clinical outcomes [death, cardiac death, myocardial infarction (MI), stroke, target vessel revascularization, and the composite of death, MI, or stroke], according to the patients' diabetic status. Results After multivariable adjustment, the risk of death [hazard ratio (HR): 1.096, 95% confidence interval (CI): 0.541-2.222; P = 0.799] and that of the composite of death, MI, or stroke (HR: 0.769, 95% CI: 0.446-1.328; P = 0.346) were similar in the DES and CABG groups. However, the rate of target vessel revascularization was significantly higher in the DES group (HR: 0.169, 95% CI: 0.079-0.358; P < 0.001). Incidence of MI (HR: 1.314, 95% CI: 0.238-7.254; P = 0.754) and that of the composite of death, MI, or stroke (HR: 1.497, 95% CI: 0.682-3.289; P = 0.315) were similar between DES and CABG in the nondiabetic group; however, in the diabetic population incidence of the composite of death, MI, or stroke (HR: 0.31, 95% CI: 0.126-0.761; P = 0.011) was significantly higher in the DES compared with the CABG group, driven mainly by the significantly higher rate of MI in the DES group (HR: 0.114, 95% CI: 0.022-0.593; P = 0.01). Rate of repeat revascularization was higher with DES compared with CABG in both diabetic and nondiabetic groups. Conclusion There was a prognostic impact of diabetes mellitus on treatment effects in patients with unprotected LMCA lesions who underwent DES or CABG. For patients with unprotected LMCA lesions, PCI with DES was an acceptable alternative to CABG at risk for higher repeat revascularization in the nondiabetic cohort, whereas in the diabetic cohort PCI with DES was inferior to CABG in terms of both safety and efficacy. Coron Artery Dis 23:322-329 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.