OBJECTIVES: Data comparing second-generation zotarolimus-eluting stents (ZES) with first-generation sirolimus- (SES) and paclitaxel-eluting stents (PES) for treatment of multivessel coronary disease (MVD) have been limited. METHODS: We performed the subgroup analysis of patients with MVD from the ZEST trial comparing ZES with SES and PES in daily clinical practice. A total of 1254 patients with MVD were treated with ZES (414 patients), SES (430 patients), and PES (410 patients). The primary end point was the composite clinical outcomes of death, myocardial infarction, and ischemia driven target vessel revascularization (TVR) at 12month after index procedure. RESULTS: Most of baseline demographics and angiographic characteristics were similar among the 3 groups. At 12 months, the rate of primary end point in the ZES group (12.2) was similar to the SES group (10.2), but superior to the PES group (17.6) (Figure 1). This outcome difference was mainly attributable to the significant difference of TVR among the groups (ZES 5.7%, SES 2.6%, and PES 8.2%) (Figure 2). During 12 months, 5 patients (1.2%) in the PES group and 3 (0.7%) patients in the ZES group had definite or probable stent thrombosis, but none in the SES group (overall P=0.04). CONCLUSIONS: For patients with multivessel coronary disease, the use of ZES resulted in similar major adverse cardiac events to SES, but in fewer events than PES.