In-stent restenosis (ISR) is a major cause of failure of percutaneous coronary intervention. The efficacy and safety of drug-coated balloon (DCB) in patients with high-risk clinical features are largely unknown. We enrolled 82 consecutive patients at high risk of bleeding with angiographically significant (diameter stenosis ≥50%) ISR of bare metal stent (BMS) or drug-eluting stent (DES), treated with paclitaxel-coated balloon. All patients presented at least one of the following criteria: high bleeding risk, neoplasm, chronic inflammatory disease, and need for noncardiac surgery. Dual antiplatelet therapy was indicated for 4 weeks after the procedure. At angiographic follow-up, overall late lumen loss was 0.24 ± 0.32 mm, with no significant difference between BMS-ISR and DES-ISR (0.25 ± 0.35 vs 0.22 ± 0.30 mm, p = 0.714). The Kaplan-Meier estimate for major adverse clinical events-free survival at 3 years was 81.4% (82.3% in BMS-ISR vs 79.4% in DES-ISR, log-rank p = 0.866). No stent thrombosis has been recorded. In conclusion, the use of paclitaxel-coated balloon seems to be associated with favorable outcomes after percutaneous coronary intervention for BMS-ISR or DES-ISR in patients with high-risk clinical features and could be considered as a reasonable option in the presence of systemic co-morbidities and contraindications to long-term dual antiplatelet therapy.