Background: Standard treatment of in-stent restenosis (ISR) which occurs after implantation of drug-eluting stents (DES) is still not established. We investigated clinical outcomes after treatment of DES ISR with implantation of another DES versus balloon angioplasty alone in a retrospective multicenter registry cohort. Methods: The study cohort included a total of 825 patients (565 males, age 63.1짹19.7 years) with DES ISR treated either with DES (n=440) or with balloon angioplasty alone (n=385). We compared clinical outcomes between the two groups. The mean follow-up duration was 726.0짹443.4 days. The primary endpoint was the incidence of major adverse cardiac events (MACE) which included all cause death, myocardial infarction (MI), target vessel revascularization (TVR). Results: Baseline clinical characteristic were similar between the two groups. However, in the DES group the initial DES which developed ISR had larger diameter (3.2짹0.6 vs. 3.0짹0.4 mm, p<0.001) and shorter lesion length (25.3짹7.5 vs. 29.0짹11.2 mm, p<0.001) compared with the Balloon group. There was no difference in the ISR pattern between the two groups. The cumulative survival free of MACE at 2 years was 85.0% vs. 77.3% (Log-Rank, p=0.003). The risk of death, MI, or TVR did not differ between the two groups. Further subgroup analyses showed no difference in clinical outcomes between Cypher versus Taxus stent or between conventional balloon versus Cutting balloon for the treatment of DES ISR. Conclusions: The use of additional DES was more effective in the treatment of DES ISR compared with balloon angioplasty alone. However, choice of DES seems to be less important in the treatment of DES ISR.