Objectives This study sought to evaluate the long-term safety and effectiveness of percutaneous coronary intervention (PCI), as compared with coronary artery bypass grafting (CABG), for unprotected left main coronary artery (LMCA) disease. Background Data on the long-term (beyond 5-year) comparative results of treatment of unprotected LMCA disease with stent implantation or CABG are limited. Methods We performed a 10-year clinical follow-up of 350 patients with unprotected LMCA disease who underwent PCI with bare-metal stents (BMS) (n = 100) or CABG (n = 250) from January 1995 to April 1999, and 5-year clinical follow-up of 395 patients with unprotected LMCA disease who underwent PCI with drug-eluting stents (DES) (n = 176) or CABG (n = 219) from January 2003 to May 2004. The primary safety end points were all-cause mortality and the composite of death, Q-wave myocardial infarction (MI), or stroke, and the primary efficacy end point was target vessel revascularization (TVR). Results In the 10-year follow-up cohort of BMS and concurrent CABG, the adjusted risks of death (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.44 to 1.50; p = 0.50) and the composite of death, Q-wave MI, or stroke (HR: 0.92; 95% CI: 0.55 to 1.53; p = 0.74) were similar between the 2 groups. The rate of TVR was significantly higher in the group that received BMS (HR: 10.34; 95% CI: 4.61 to 23.18; p < 0.001). In the 5-year follow-up cohort of DES and concurrent CABG, there was no significant difference in the adjusted risk of death (HR: 0.83; 95% CI: 0.34 to 2.07; p = 0.70) or the risk of the composite outcome (HR: 0.91; 95% CI: 0.45 to 1.83; p = 0.79). The rates of TVR were also higher in the DES group than the CABG group (HR: 6.22; 95% CI: 2.26 to 17.14; p < 0.001). Conclusions For the treatment of unprotected LMCA disease, PCI with stent implantation showed similar long-term mortality and rates of death, Q-wave MI, or stroke. However, stenting, even with DES, was associated with higher rates of repeat revascularization than was CABG.