BACKGROUND Although second-generation drug-eluting stent (DES) has been designed to ensure better safety and efficacy, long-term outcomes of large randomized trial comparing first vs. second-generation DES in daily clinical practice have been limited. METHODS The ���all-comers��� design, ZEST trial was designed to compare the second-generation zotarolimus-eluting stent with the first-generation sirolimus-and paclitaxel-eluting stent for percutaneous coronary revascularization (PCI) in daily practice, and 2645 patients were enrolled. We performed 2-year follow-up to evaluate relative long-term safety and efficacy. The primary outcome was a composite of major adverse cardiac events (MACE; death, myocardial infarction [MI], and ischemia-driven target-vessel revascularization [TVR]). RESULTS Two-year clinical outcomes were available in 2,552 patients (96.5%) patients. At 24 months, the zotarolimus-stent group showed similar rates of MACE compared with the sirolimus-stent SES group (11.3% vs. 9.9, P=0.43), and significantly fewer MACE than the paclitaxel-stent group (11.3% vs. 15.2, P=0.01). The incidence of death or MI was similar among the groups (zotarolimus- vs. sirolimus- vs. paclitaxel-stent, 7.5% vs. 6.2% vs. 7.8%, respectively, P=0.35), but the rate of TVR significantly differ (zotarolimus- vs. sirolimus- vs. paclitaxel-stent, 6.0% vs. 3.1% vs. 8.6%, respectively, P<0.001). The rates of definite or probable stent thrombosis did not significantly differ among the groups (zotarolimus- vs. sirolimus- vs. paclitaxel-stent, 0.7% vs. 0.2% vs. 0.8%, respectively, P=0.17). CONCLUSIONS During 2-year long-term follow-up of this large-scale, practical randomized trial, the use of zotarolimus-stents resulted in similar rates of MACE compared with sirolimus-stents, and in fewer MACE compared with paclitaxel-stents.