BACKGROUND Newer-generation everolimus-eluting stents (EES) have improved angiographic and clinical outcomes compared with first-generation paclitaxel-eluting stents. However, it remains unclear whether there are differences in the safety and efficacy between everolimus-eluting and sirolimus-eluting stents (SES) in real-world practice of stent procedures. METHODS We prospective enrolled consecutive 6166 patients who received EES (3081 patients) and SES (3085 patients) in 2008 and 2009, using data from the Interventional Cardiology Research Incooperation Society-Drug-Eluting Stents (IRIS-DES) Registry, from 55 cardiac centers. The primary outcome was a composite of death, nonfatal myocardial infarction (MI), or target-vessel revascularization (TVR). To account for differences in patients��� severity of illness, angiographic, and procedural characteristics, the rates of adverse outcomes are adjusted by means of Inverse-Probability-of-Treatment Weights (IPTW) using propensity scores. RESULTS During follow-up of mean 18 months, the two study groups did not differ significantly in crude risk of the primary composite outcome (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.84-1.12, P=0.97). After adjustment for differences in baseline risk factors, the adjusted risks for primary outcome did not differ between patients who received EES and those who received SES (HR, 0.96; 95% CI, 0.82-1.12, P=0.60). In addition, there was no overall difference between the groups in the adjusted risks of the individual end points of death (HR, 0.93; 95% CI, 0.67-1.30, P=0.68), MI (HR, 0.97; 95% CI, 0.79-1.18, P=0.74), and TVR (HR, 1.10; 95% CI, 0.82-1.49, P=0.51). The adjusted risk of stent thrombosis was also similar among the two group (HR, 1.16; 95% CI, 0.47-2.84, P=0.75). CONCLUSIONS In this large-scale, multi-center, prospective observational cohort in ���real-world��� PCI patients, EES resulted in similar rates of clinical safety and efficacy outcomes as compared with SES.