Percutaneous coronary intervention with drug-eluting stents (DES) may achieve midterm outcomes comparable to coronary artery bypass grafting (CABG) for unprotected left main coronary artery disease, but few real-world, long-term studies have been reported. In this study, 376 patients with unprotected left main coronary artery disease who underwent DES implantation (n = 131) or CABG (n = 245) were evaluated, and outcomes were compared using propensity analyses to adjust for baseline differences. Overall, 367 patients (98%) had complete clinical follow-up for a median of 4.0 years (interquartile range 3.2 to 4.7). Although the overall sample size was limited, there was a trend toward lower mortality with DES versus CABG in unadjusted (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.20 to 1.22, p = 0.13), multivariate-adjusted (HR 0.37, 95% CI 0.13 to 1.09, p = 0.07), and propensity score-adjusted (HR 0.34, 95% CI 0.12 to 1.03, p = 0.06) analyses. Treatment with DES was associated with a higher rate of target-vessel revascularization (TVR; 18% vs 9%, p = 0.02). However, ischemic TVR was not significantly different between the 2 groups (25% vs 39%, p = 0.15) in patients who received angiographic follow-up. No differences were detected in the occurrence of composite major adverse cardiac and cerebrovascular events between DES and CABG (27% vs 22%, p = 0.42). In conclusion, during 4-year follow-up, overall composite major adverse cardiac and cerebrovascular events were similar after DES and CABG treatment of unprotected left main coronary artery disease, with a trend toward lower mortality after percutaneous coronary intervention with DES. DES were associated with a higher rate of TVR compared to CABG, but ischemic TVR was not significantly different between the 2 groups.