Background: The best way to treat in-stent restenosis (ISR) after drug-eluting stent (DES) implantation remains unclear. The aim of this study was to evaluate angiographic restenosis and target lesion revascularization (TLR) at 8 months after intervention in patients with DES-ISR, and to identify predictive factors of subsequent TLR after treatment of DES-ISR., Methods and Results: A total of 100 patients with 105 lesions underwent subsequent intervention for DES-ISR between April 2004 and January 2009. At baseline, focal and diffuse ISR were observed in 76.2% and 23.8%. DES-ISR was treated by five modalities: sirolimus-eluting stent (n=42); paclitaxel-eluting stent (n=24); balloon angioplasty (n=23); cutting balloon angioplasty (n=14); and bare-metal stent (n=2). Angiographic follow-up data were available for 95 lesions (91%). The rates of angiographic restenosis and TLR were 37.9% and 33.3%. Late loss of sirolimus-eluting stent, paclitaxel-eluting stent, cutting balloon, and balloon angioplasty were 0.50 mm, 0.49 mm, 0.93 mm, and 1.10 mm. By multivariate analysis, totally occluded ISR (OR 15.43, p=0.0005), diabetes mellitus (OR 3.45, p=0.02), and re-stenting with DES (OR 0.14, p=0.0002) were identified as independent predictors of TLR., Conclusions: The restenosis rate was significant in this cohort of patients with DES-ISR. Angiographic pattern of DES-ISR and diabetes mellitus are the most important predictors of TLR, whereas re-stenting with DES is protective., (Copyright 2010 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)