Even though drug-coated balloon (DCB) angioplasty has emerged as a treatment option for drug-eluting stent in-stent restenosis (DES–ISR), the most effective treatment strategy for DES–ISR is still under debate. Therefore, we compared long-term clinical outcomes following DCB treatment of DES–ISR with those following 2nd-generation drug-eluting stent (DES) treatment. We identified 248 DES–ISR lesions in 238 patients that were treated with either 2nd-generation DES implantation (n = 56) or DCB angioplasty (n = 192). We compared the incidences of major adverse cardiac events (MACEs) in the two groups during the 2-year period following treatment. MACE was defined as cardiac death, non-fatal myocardial infarction, or target-vessel revascularization. The percentage of patients with diabetes and the mean age of patients in the DCB group were greater than in the DES group. The DCB group also had a smaller reference vessel diameter. The DES group had a larger post-intervention minimal luminal diameter. We found no significant difference in the MACE rate between the two groups during the 2 years following treatment (11.0 % in the DCB group vs. 8.9 % in the DES group, p = 0.660). Reference segment diameter was the only independent predictive factor for MACE in the post-treatment period (hazard ratio 0.35, 95 % confidence interval: 0.15–0.82, p = 0.016). Clinical efficacy of DCB angioplasty for treatment of DES–ISR was comparable to that of 2nd-generation DES implantation as measured by the rate of MACEs in the two groups. Reference segment diameter was the only statistically significant independent predictor for MACE in the 2-year period following treatment.