The effectiveness of excimer laser atherectomy (ELA) combined with drug-coated balloon (DCB) for de novo femoropopliteal artery disease (FPAD) is currently unknown. This case series evaluated the clinical outcomes of ELA combined with DCB in de novo FPAD from a real-world clinical perspective.We conducted a retrospective study of patients treated with ELA + DCB for de novo FPAD between November 2016 and January 2020. The primary efficacy endpoint was the initial patency rate, secondary endpoints included target lesion revascularization without clinically driven target-lesion revascularization (CD-TLR) and technical success. Primary safety endpoints included all-cause death, unplanned major amputation, and postoperative complications.The mean follow-up was 37.8 ± 25.3 months and included 56 consecutive patients (68.23±8.01 years, 41 men). Forty-three patients had lifestyle-restricted claudication and 13 patients had critical limb threatening ischemia. The mean length of the lesion was 178.41 mm in all patients. The total lesion occlusion rate was 48.2 (n=27), and the overall technical success rate was 100%. The 12-month, 24-month, 36-month and 48-month primary patency rates of ELA + DCB group were 75%, 66.1%, 58.9% and 42.8%, respectively. Freedom from CD-TLR at 12, 24, 36 and 48 months was 83.9%, 80.3%, 76.8% and 57.1%, respectively.In real-world clinical practice, ELA + DCB appears to be a safe and effective endovascular treatment for de novo FPAD, with a low rate of freedom from CD-TLR and a good patency rate.Copyright © 2023. Published by Elsevier Inc.