This study was conducted to compare the clinical outcomes of drug-eluting stents (DESs) with those of standard bypass surgery for the treatment of patients with left main lesions in a single-center experience. From January 2000 to October 2005, a total of 96 patients with significant unprotected left main disease were treated with DES implantation, and 245 with bypass surgery. Baseline features, such as Euroscore, were similar between groups, except for diabetes and hypertension, which were more frequent in the surgical group. The combination of death, Q-wave myocardial infarction, stroke, and repeated revascularization (major adverse cardiac and cerebrovascular events [MACCEs]) at 30 days occurred in 2.1% after DES implant and 9.0% after surgery (p=0.03). At 1 year, DES-treated patients more frequently needed repeat revascularization (5.2% vs 0.8%; p=0.02), although combined MACCE rates were similar (10.4% for DES, 11.4% for surgery; p=0.50). Moreover, after a mean follow-up of 1.3+/-0.8 and 3.2+/-1.6 years for the DES and surgical groups, there were no significant differences in MACCEs, respectively. In conclusion, in our experience, percutaneous treatment of patients with unprotected left main disease with DESs provided similar clinical results compared with surgical revascularization at a midterm follow-up.