BACKGROUND: Although percutaneous coronary intervention with everolimus-eluting stent (EES) implantation for native coronary artery disease has favorable results compared to first-generation drug-eluting stents, outcomes with EES for the treatment of in-stent restenosis (ISR) are unknown. METHODS: The Xience V USA is a prospective multicenter registry evaluating outcomes in patients treated with EES. Here, we present the 12-month clinical outcomes in patients who received EES for the treatment of ISR and non-ISR. The primary outcome was the composite of target lesion failure (cardiac death, target vessel myocardial infarction (MI), or target lesion revascularization). Secondary outcomes were MI, target lesion revascularization (TLR), and stent thrombosis (ST). RESULTS: In this registry, a total of 383 patients (64.4 ± 11.4 years; 68.4% male) received revascularization for single-vessel ISR and 4832 patients (64.4 ± 11.0 years; 69.0% male) received revascularization for non-ISR lesions. At 1 year, target lesion failure was 10.9% in the ISR group and 4.9% in the non-ISR group. MI, TLR, and definite ST rates were higher in the ISR group (MI, 2.2% ISR group and 1.6% non-ISR group; TLR, 10.3% ISR group and 2.9% non-ISR group; definite/probable ST, 1.98% ISR group and 0.36% non-ISR group). However, these differences ceased to exist when case-control matched patients in the non-ISR group were studied (target lesion failure, 8.8% ISR vs 7.4% non-ISR; cardiac death or MI, 2.7% ISR vs 1.4% non-ISR; TLR, 7.8% ISR vs 7.1% non-ISR; and definite/probable ST, 1.03% ISR vs 0.69% non-ISR). CONCLUSION: The treatment of ISR with EES appears to be safe and efficacious at 1 year. Compared to the non-ISR group, target lesion failure was much higher, indicating a higher risk profile of these patients. However, these differences ceased to exist with case-controlled matching.