There are no data available comparing the real-world, long-term clinical outcomes of drug-eluting balloon (DEB) angioplasty and drug-eluting stent (DES) implantation in DES in-stent restenosis (ISR) lesions. We aimed to compare the real-world, long-term data available between DEBs and DESs in DES-ISR lesions. We analyzed consecutive DES-ISR lesions (225 lesions from 205 patients; male: 66.3%; mean age: 62.4 years) treated with either DEB or DES. The primary endpoint was target lesion revascularization (TLR), and the primary safety endpoint was the lesion-oriented composite outcome (LOCO). The LOCO is composed of cardiac death, myocardial infarction, and target lesion thrombosis during follow-up. During the 7-year follow-up period, TLR did not differ significantly between the DEB (n = 108) and the DES groups (n = 117) (HR: 1.07; 95% CI: 0.59–1.93, p = 0.83). The LOCO was significantly lower in the DEB group compared to the DES group (HR: 0.40; 95% CI: 0.16–0.98, p = 0.04), which was mainly driven by the lower levels of myocardial infarction (HR: 0.24; 95% CI: 0.06–0.94, p = 0.04) and the absence of target lesion thrombosis in the DEB group (vs. DES group 6%, p = 0.02). Additionally, cardiac death was found to be similar between the DEB and DES groups (HR: 0.56; 95% CI: 0.18–1.75, p = 0.32). DEB angioplasty showed favorable safety with a similar efficacy to that of DES implantation in DES-ISR lesions during the long-term follow-up period.