Objectives: To assess clinical performance of the second-generation Endeavor Resolute® drug-eluting stents (DES) in an unrestricted high-risk cohort of patients. Background: New-generation DESs aim to further increase its clinical safety and efficacy by means of more biocompatible components limiting inflammatory response, assuring strut coverage and preserving endothelial vascular function. Methods: Between January 2008 and April 2009 820 unselected consecutive high-risk patients (1,352 lesions) treated with the Endeavor Resolute® stent were enrolled in an independent multicenter registry. Primary end-points of this registry were immediate procedural outcome, incidence of target lesion failure (TLF, defined as composite of cardiac death, myocardial infarction, and target lesion revascularization) and rate of ARC stent thrombosis at 12-months follow-up. Results: High-risk patient/lesion profile included acute coronary syndrome diagnosis in 57% of patients, diabetes mellitus in 23% and ACC/AHA type B2/C lesion in 74%. Endeavor Resolute® stent was used in an off-label indication in 52% of cases with stent/patient ratio of 1.93 and average stented segment of 39.8±26.6mm. Immediate procedural success was accomplished in 96.0% of cases and at median 12-month follow-up TLF rate was 7.1% with 4.0% of clinically driven repeat revascularizations and 1.1% of definite/probable stent thrombosis incidence. At multivariable analysis, nor off-label Endeavor Resolute® stent use or multiple stent implantations were associated to an increased risk of adverse events. Conclusions: Extensive use of the new Endeavor Resolute® stent was associated with favorable procedural and 12-month outcomes despite the treatment of unselected complex clinical and anatomical presentation. Endeavor Resolute® stent showed excellent safety and efficacy profile also in off-label indications. © 2011 Wiley Periodicals, Inc.