Objective: We aimed to investigate the clinical outcomes of patients with recurrent drug eluting stent (DES) in-stent restenosis (ISR) (multimetal-layered ISR) treated with Drug-coated balloon (DCB). Backgrounds: Little is known about the efficacy of DCB treatment for multimetal-layered ISR. Methods: The study population comprised 123 patients (145 lesions) who underwent DCB angioplasty for multimetal-layered ISR lesions. Two serial angiographic follow-up were routinely planned for the patients (at 6 and 18 months after procedure). Results: Early follow-up angiography was performed for 132 lesions (91.0%). Recurrent restenosis occurred 36 lesions (27.3%) and target lesion revascularization (TLR) was performed for 26 lesions (19.7%). Late follow-up angiography was performed for 94 lesions (88.7%) of the remaining 106 lesions (excluding TLR lesions). Late recurrent restenosis occurred 25 lesions (26.6%) and TLR was performed for 16 lesions (17.0%). Proportion of right coronary artery (RCA) and incidence of previous stent fracture were significantly higher in patients with recurrent restenosis (43.3% vs. 66.7%, p = 0.008, and 6.0% vs. 30.0%, p = 0.001). Multivariate analysis revealed RCA ostial lesion (odds ratio [OR]: 4.28; 95% confidence interval [CI]: 1.06 to 22.0; p = 0.04) and previous deployed stent fracture (OR: 6.14; 95% CI: 2.04 to 23.1; p = 0.001) was an independent risk factor of recurrent restenosis. Cumulative event rates of TLR and MACE (All-cause mortality, myocardial infarction, and TLR) were significantly higher in previous stent fracture group (60.6% vs 27.0%, log rank p = 0.007 and 65.0% vs. 35.3%, log rank p = 0.007). Conclusion: Our study suggests that previous stent fracture was a risk factor of recurrent restenosis after DCB angioplasty for multimetal-layered ISR. Further study was necessary to identify the optimal treatment for multimetal-layered ISR with stent fracture.