Background: We performed the present systematic review and meta-analysis of randomized and nonrandomized comparative studies in an attempt to compare the safety and efficacy of drug-eluting stents with coronary artery bypass grafting for patients with coronary artery disease. Methods: Twenty-five eligible comparative studies (1 randomized and 24 nonrandomized) were assessed. Two reviewers independently appraised each study. Meta-analysis was performed by combining the results of reported incidence of morbidity, mortality, and repeat revascularization. The relative risk was used as a summary statistic. Results: In these 25 studies 34,278 patients were compared, of whom 18,538 received drug-eluting stents and 15,740 underwent coronary artery bypass grafting. It must be acknowledged that this comparison represented a selected group of patients who received drug-eluting stents or underwent coronary artery bypass grafting. The accumulative incidences of all-cause mortality at 12 months (4.5% vs 4.0%, P = .92) and 24 months (6.2% vs 8.4%, P = .27) and 30-day myocardial infarction (1.4% vs 2.0%, P = .60) were similar, respectively, between the drug-eluting stent and coronary artery bypass grafting groups. Drug-eluting stents were associated with lower rates of all-cause mortality at 30 days (0.9% vs 2.3%, P < .001), stroke (0.4% vs 1.7%, P < .001), and 30-day major adverse cardiac and cerebrovascular events (3.6% vs 5.5%, P < .04). However, the coronary artery bypass grafting group had a lower incidence of postprocedural myocardial infarction (5.5% vs 4.7%, P = .03), repeat revascularization (22.2% vs 4.1%, P < .001), and 12-month major adverse cardiac and cerebrovascular events (16.7% vs 10.5%, P < .001). Subgroup analysis of patients with multivessel coronary artery disease showed similar results. Conclusions: Drug-eluting stents are associated with less periprocedural risks but a higher incidence of postprocedural myocardial infarction, repeat revascularization, and 12-month major adverse cardiac and cerebrovascular events compared with coronary artery bypass grafting.