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Background: In the drug-eluting stent era, the best strategy to treat Medina 001 lesion remains unestablished. This is the first prospective registry assessing the efficacy and safety of the second-generation drug-coated balloon in patients with side-branch ostial lesion., Methods: Forty-nine patients with de novo Medina 001 lesion and associated myocardial ischemia were treated with second-generation drug-coated balloon-Dior balloon catheter (Eurocor GmbH, Bonn Germany), and prospectively included in this study. After mandatory pre-dilatation, a paclitaxel-eluting balloon was inflated for a minimum of 45 seconds. Left main bifurcation, severely calcified lesions and cardiogenic shock, were the only exclusion criteria., Results: The inclusion period was 2.7 years. Mean age was 62 ± 12 years old, 41% diabetic, 65% presented with acute coronary syndrome. The most common vessel treated was the first diagonal (50%). Pre-dilatation with a cutting balloon was used in 59%. Angiographic success was 86% (in 14% a bare metal stent was implanted because of acute recoil [n = 5] or coronary dissection more than type B [n = 2]). At a mean of 12.2 ± 2.2 months, major cardiac adverse events rate was 14.3% (1 myocardial infarction, 0 cardiac deaths, 7 target lesion revascularization). There was no thrombosis or occlusion. At a mean of 7.2 ± 1.1 months, binary restenosis was 22.5% (n = 7) with a late loss of 0.32 ± 0.73 mm., Conclusion: Medina 001 lesion is an infrequent type of coronary lesion. Drug-coated balloon-Dior is a safe and technically easy therapeutic option, associated with acceptable mid-term clinical outcomes. (J Interven Cardiol 2016;29:285-292)., (© 2016, Wiley Periodicals, Inc.)