Background While EES have proven superior to paclitaxel-eluting stents, it remains uncertain whether EES improve clinical outcomes compared to SES, which are the most efficacious among the first-generation drug-eluting stents. We performed a meta-analysis of randomized trials comparing the efficacy and safety of everolimus-eluting stents (EES) versus sirolimus-eluting stents (SES) in patients undergoing percutaneous coronary intervention. Methods From online and offline search until December 2011, we identified 11 randomized trials (total 12,869 patients). The primary endpoint was major adverse cardiac events. Results The risk of major adverse cardiac events did not differ significantly between the patients treated with EES versus SES OR, 0.90 (95% CI, 0.77-1.04); P = .162. However, we found a significant reduction in the risk of repeat revascularization in the EES arm OR, 0.85 (95% CI, 0.71-1.00); P = .047. There were no significant differences regarding the risk of cardiac death OR, 0.97 (95% CI, 0.74-1.27); P = .834, or myocardial infarction OR, 0.95 (95% CI, 0.75-1.20), P = .656. The risk of definite or probable stent thrombosis tended to be lower OR, 0.68 (95% CI, 0.45-1.02); P = .065, while definite ST was significantly lower OR, 0.44 (95% CI, 0.25-0.80); P = .007 with EES. Conclusions In a large systematic overview of comparative trials involving percutaneous revascularization with drug-eluting stents, treatment with EES significantly reduced the risk of repeat revascularization and definite ST compared to SES. We found no significant differences in the risk of cardiac death or myocardial infarction.