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This study assesses clinical outcomes after drug-eluting balloon treatment for recurrent in-stent restenosis lesions based on the number of metallic layers.We enrolled 304 consecutive patients (333 lesions) treated with percutaneous coronary intervention using drug-eluting balloon for in-stent restenosis lesions between March 2014 and June 2015. Per the number of stent layers previously implanted to the lesion, the patients were categorized into 3 groups, 1 stent layer (1L), 166 patients; 2 stent layers (2L), 87 patients; and ≥3 stent layers (≥3L), 51 patients. The end points were major adverse cardiovascular events (MACE), including cardiac death, target lesion revascularization, myocardial infarction, and definite or probable stent thrombosis. No significant differences were observed in patients’ baseline characteristics among the groups. The 1-year MACE and target lesion revascularization rates were significantly higher in the ≥3L group than those in the 1L and 2L groups (MACE: 1L, 16.9%; 2L, 16.1%; and ≥3L, 43.1%, P<0.01; target lesion revascularization: 1L, 14.5%; 2L, 14.9%; and ≥3L, 41.2%, P<0.01). The multivariable Cox regression analysis revealed that the number of metallic layers (≥3L compared with 1L; hazard ratio, 3.17; [95% CI, 1.75–5.76]; P<0.01 and hemodialysis [hazard ratio, 2.21; (95% CI, 1.12–4.36); P=0.02]) were independent predictors for MACE. No significant differences were observed in the occurrence of cardiac death among the groups (P=0.34).Seemingly, drug-eluting balloon is less effective for ≥3L in-stent restenosis lesions. Hemodialysis and in-stent restenosis with the number of metallic layers are independent predictors for MACE.