Background and objectives Second generation drug-eluting stents (DES) has been shown non-inferior or superior efficacy and safety compared with first generation DES in the treatment of coronary lesions. The aims of this study were to compare the efficacy and safety between everolimus-eluting stents (EES) and zotarolimus-eluting stents (ZES) in patients with acute myocardial infarction (AMI). Methods In this multi-center, prospective randomized and noninferiority trial, 500 patients (189 non-ST-segment elevation AMI and 311 ST-segment elevation AMI) have been enrolled in a 1:1 fashion according to the type of stent (EES vs. ZES). The primary end point was major adverse cardiac events (MACE), defined as the composite of death from cardiovascular causes, re-infarction, and ischemia-driven target vessel revascularization (TVR) at 12 months. The secondary endpoints were stent thrombosis within 12 months and in-stent late luminal loss (LL), and degree of restenosis at 9-month angiographic follow-up. RESULTS One-year clinical and 9-month angiographic follow-ups were completed in 82% and 42.3% patients, respectively up to this point (July 15, 2011). The MACE rate was similar in EES and ZES groups (4.1% vs. 5.8%, P = 0.252 for noninferiority). There were no significant between-group differences in the rate of death from cardiac causes, re-infarction, or TVR. The rate of stent thrombosis was 0.4% in the EES group and 2.1% in the ZES group (P = 0.121). It was comparable in the degree of in-stent restenosis between two stent groups (18.08짹14.65% for EES vs. 21.41짹21.96% for ZES, P=0.193). In-stent late lumen loss was 0.23짹0.35mm in the EES group and 0.24짹2.14mm in the ZES group (P=0.781). CONCLUSIONS ZES was noninferior to EES in safety and efficacy at 12 months in patients with AMI.