Recent studies have suggested that percutaneous coronary intervention (PCI) in patients with unprotected left main coronary artery (LMCA) disease renders outcomes comparable to those from coronary artery bypass grafting (CABG). It is necessary to stratify individual patient risk and select the optimal revascularization strategy. We compared the clinical outcomes of patients with unprotected LMCA disease who had undergone PCI with drug-eluting stents or CABG. We identified 462 patients who were treated from January 2003 to December 2006 for unprotected LMCA or LMCA-equivalent disease: 257 had undergone CABG and 205 had undergone PCI with drug-eluting stents. Analyses using propensity scores were performed to minimize the selection bias in the present observational study. After a median follow-up of 33.5 months, no significant difference was found between the CABG and PCI groups in the risk of death (12.1% vs 14.1%, respectively; p = 0.428) or the risk of a composite of death, myocardial infarction, or cerebrovascular accident (17.5% vs 20.0%, respectively; p = 0.434). The rate of major adverse cardiac and cerebrovascular events was significantly lower in the CABG group than in the PCI group (21.8% vs 35.1%, respectively; p = 0.001); the difference was mainly driven by a decrease in the rate of repeat revascularizations (5.1% vs 22.4%; p <0.001). The analyses after propensity score adjustment and matching corroborated the crude group results. In conclusion, PCI with drug-eluting stents showed a safety profile comparable to that of CABG in patients with unprotected LMCA disease. However, the risk of repeat revascularization was significantly greater in the PCI group.