BACKGROUND Studies comparing the next-generation drug-eluting stents with first-generation sirolimus- and paclitaxel-eluting stents for coronary revascularization in all-comers populations have been limited. METHODS We performed a single-blind, multicenter, prospectively randomized trial to compare zotarolimus-eluting stents with sirolimus- and paclitaxel-eluting stents in 2,645 patients undergoing percutaneous coronary intervention. The primary end point was a composite of major adverse cardiac events (death, myocardial infarction, and ischemia-driven target-vessel revascularization) at 12 months. A noninferiority comparison (zotarolimus- vs. sirolimus-stents) and a superiority comparison (zotarolimus- vs. paclitaxel-stents) were performed for the primary end point. RESULTS Baseline clinical and angiographic characteristics were similar in the three groups. At 12 months, the zotarolimus-stent group showed noninferior rates of major adverse cardiac events compared with the sirolimus-stent group (10.2% vs. 8.3%, P for non-inferiority=0.01, P for superiority=0.17), and significantly fewer major adverse cardiac events than the paclitaxel-stent group (10.2% vs. 14.1%, P for superiority=0.01). There was a nonsignificant trend in favor of the zotarolimus-stent group in the rate of death or myocardial infarction (zotarolimus vs. sirolimus vs. paclitaxel, 5.8% vs. 6.9% vs. 7.6%, P=0.31). The incidence of stent thrombosis was significantly lower in the sirolimus-stent group (zotarolimus vs. sirolimus vs. paclitaxel, 0.7% vs. 0% vs. 0.8%, P=0.02). CONCLUSIONS In this large-scale, practical randomized trial, the use of zotarolimus-eluting stents resulted in similar rates of major adverse cardiac events compared with sirolimus-eluting stents, and in fewer major adverse cardiac events compared with paclitaxel-eluting stents during 1 year of follow-up.