Abstract Objective To investigate the precise changes in the lumen and lesions, and clinical outcomes after DCB treatment for de-novo coronary lesions exceeding 2.5 mm in diameter through a detailed analysis of OCT. Methods This is a prospective study including 53 consecutive patients with 55 de-novo coronary lesions, who underwent DCB angioplasty-only between January 2021 and April 2022. Quantitative coronary angiography (QCA) and OCT were performed before percutaneous coronary interventions (PCI), immediately after PCI, and at 6-9 months follow-up after PCI. Target lesion failure (TLF) was the primary endpoint of the present study. Multivariate logistic regression analysis was performed to identify the predictors or risks for late lumen enlargement (LLE). Results A total of 52 patients were successfully treated with DCB. The median follow-up was 7 months, and the incidence of TLF was 7.5%. After the DCB procedure, 43 patients had their scheduled angiographic and OCT examination. QCA demonstrated that the late lumen loss was -0.79 ± 0.28 mm. OCT demonstrated LLE in 79.1% and dissection healing in 65.1% of lesions. After multivariable logistic analysis, type B dissection (odds ratio [OR] 2.92, 95% confidence interval [CI] 1.34-7.41, p = 0.037) was found to be a predictor of LLE, but lipid plaque (OR 0.09, 95% CI 0.01-0.63, p = 0.015) was a risk of LLE. Conclusions This is the first and largest prospective study to assess the outcomes of DCB treatment for de-novo coronary lesions exceeding 2.5 mm in diameter and the detection of significant vessel enlargement and dissection healing guide by OCT. DCB could be a novel, safe and effective treatment for de-novo coronary lesions exceeding 2.5 mm in diameter through a detailed analysis of OCT.Representative coronary angiography (CAGRepresentative optical coherence tomogra