The aim of this study was to evaluate late safety and efficacy outcomes among patients enrolled in clinical trials comparing Endeavor zotarolimus-eluting stents (E-ZES) (Medtronic, Inc., Santa Rosa, California) with first-generation drug-eluting stents (DES) and bare-metal stents (BMS). BACKGROUND: Despite demonstration of higher angiographic luminal loss and restenosis with E-ZES compared with alternative DES, whether differences in these early angiographic measures translate into more disparate late clinical events is uncertain. METHODS: Among 3,616 patients undergoing percutaneous coronary revascularization in 5 registration trials, late safety and efficacy events were compared between E-ZES (n = 2,132) versus sirolimus- or paclitaxel-eluting stents (n = 888) or BMS (n = 596). RESULTS: Compared with a parallel cohort of patients treated with first-generation DES and BMS, 5-year rates of cardiac death/myocardial infarction (MI) (5.8 vs. 8.8 DES, p = 0.003; vs. 8.4 BMS, p = 0.02) and major adverse cardiac events (16.1 vs. 20.6 DES, p = 0.009; vs. 24.6 BMS, p <0.001) were significantly lower with E-ZES. The E-ZES was associated with significantly lower target lesion revascularization (TLR) compared with BMS (7.4 vs. 16.3 , p <0.001) but similar to comparator DES (7.4 vs. 8.1 , p = 0.63). Despite higher TLR in the first year with E-ZES compared with DES, between 1- and 5-year follow-up, rates of cardiac death/MI, TLR, and definite/probable stent thrombosis were significantly lower with E-ZES. CONCLUSIONS: Over 5 years, significant differences in cardiac death/MI and composite endpoints favored treatment with E-ZES over comparator BMS and DES. Rates of clinical restenosis and safety events, including stent thrombosis beyond the first year of revascularization, remain stable with E-ZES, leading to significant differences compared with first-generation DES.