BACKGROUND: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) often requires extensive metal implantation, which may impair vascular vasomotor function and increase the risk for late adverse events. Drug-coated balloon (DCB)-based strategies offer stent-free or stent-reduced alternatives, but the acute and mid-term efficacy and safety of this approach in the CTO setting are not yet demonstrated. OBJECTIVES: The aim of this study was to evaluate the clinical outcomes of DCB revascularization strategies in a large, real-world CTO patient population at expert centers. METHODS: PICCOLETO X was a multicenter, ambispective, all-comers registry including consecutive CTO PCI patients treated with at least 1 DCB across 21 international centers. The primary endpoint was target vessel failure at 12 months, defined as a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization. The procedural data and outcomes of DCB-only vs DCB + stent strategies, applying a propensity score matching model using a 1:1 nearest neighbor algorithm with a caliper width of 0.2 to overcome baseline differences. RESULTS: A total of 938 patients were included (DCB only, n = 476; DCB + stent, n = 462). The mean age was 64.6 ± 10.9 years. 73.7% were men, and 38.4% had diabetes. Lesion length ≥20 mm was present in 69%, and 51% of patients had calcified CTOs. As for the in-hospital outcome, acute kidney injury occurred in 3.6% of patients, perforations in 5%, and periprocedural myocardial infarction in 1.8%, with no differences among strategies. At 12 months, target vessel failure occurred in 9.5% of the patient population, with no differences both in the overall cohort (10.6% in the DCB-only group vs 8.4% in the blended group; P < 0.399) and after propensity score matching (6.2% in the DCB-only arm vs 8.8% in the blended arm; P < 0.367) and with no differences for all the determinants of this composite endpoint. CONCLUSIONS: In a real-world cohort of patients undergoing CTO PCI, a DCB-based strategy, either alone or in combination with stents, was associated with favorable 1-year clinical outcomes. No significant differences were observed between DCB-only and blended treatment with a stent.