Coronary dissection is a potential occurrence after lesion preparation for percutaneous coronary intervention (PCI). Unlike stents, drug-coated balloons (DCBs) do not allow to cover dissections, thus demanding an assessment of their safety in this setting. This study aimed to evaluate the incidence, predictors, and clinical outcomes of dissections occurring with DCB-based PCI for de novo coronary artery disease. Consecutive patients with de novo coronary artery disease who underwent PCI with intention-to-treat DCB angioplasty, with or without stent implantation, were retrospectively enrolled between 2018 and 2022 at 2 Italian centers. The decision whether to leave a dissection untreated or to proceed with bail-out stenting was based on a combined angiographic evaluation of Thrombolysis In Myocardial Infarction flow, residual minimal lumen diameter, and persistent extraluminal contrast hang-up. The primary end point at 2-year follow-up was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization. Among 522 DCB-treated lesions (466 patients), dissections were angiographically evident in 39.1% of cases, with 21.1% which underwent bail-out stenting and 78.9% left untreated. The incidence of bail-out stenting increased from type A to type E dissections (p for trend <
0.001). Left anterior descending artery involvement (odds ratio 1.64, 95% confidence interval 1.12 to 2.39) was the strongest risk factors for dissection. Target lesion failure at 2 years occurred in 2.7% of lesions with untreated dissection compared with 4.2% of those with no dissection (log-rank p = 0.324). In conclusion, coronary dissections often complicate PCI with DCB angioplasty but do not correlate with increased risk of adverse events at midterm follow-up.