Background— The optimal percutaneous treatment of drug-eluting stent (DES) in-stent restenosis (ISR) and the correlates for recurrent DES ISR remain unclear. Methods and Results— From 2003 to 2008, 563 patients presenting with recurrent symptoms of ischemia and angiographic ISR after DES implantation were included. Of these, 327 were treated with re-DES (58.1%), 132 underwent vascular brachytherapy (23.4%), and 104 were treated with conventional balloon angioplasty (18.5%). Variables associated with target lesion revascularization at 1 year were explored by individual proportional hazard models. This population presents a high prevalence of comorbidities, including diabetes (43.7%), previous myocardial infarction (MI) (45.8%), coronary bypass graft surgery (39.2%), chronic renal failure (18.8%), and heart failure (17.3%). Baseline clinical characteristics were balanced among the 3 groups; however, patients undergoing vascular brachytherapy presented with more complex lesions and a higher prevalence of prior stent/vascular brachytherapy failure than did the rest of the population. The overall incidence of recurrent DES failure at 1-year follow-up was 12.2%, which was similar among the 3 groups ( P =0.41). The rate of the composite end point (death, Q-wave-MI and target lesion revascularization) at 1-year follow-up was 14.1% for re-DES, 17.5% for vascular brachytherapy, and 18.0% for conventional balloon angioplasty ( P =0.57). After univariable analysis tested the traditional known covariates related to ISR, none of them were associated with repeat target lesion revascularization. Conclusions— Recurrence of ISR after DES treatment failure is neither infrequent nor benign, and optimal therapy remains unclear and challenging. Given the absence of traditional risk factors for ISR in this population, further research is required to elucidate both the correlates involved in DES ISR and the optimal treatment for this condition.