To evaluate the safety and efficacy of excimer laser ablation (ELA) combined with drug-coated balloon(DCB)in the treatment of Chronic limb-threatening ischemia (CLTI) patients with de novo and in-stent restenosis (ISR) lesions in the femoropopliteal artery.A retrospective, single-center analysis was performed on data collected between January 2017 and December 2021. The study included CLTI patients who underwent treatment with ELA combined with DCB for de novo and ISR lesions in the femoropopliteal artery. The primary endpoint was the 24-month primary patency rate. Secondary endpoints included technical success rate and the incidence of major adverse events (MAEs), defined as death, major limb amputation, or target vessel revascularization.A total of 44 patients were included in the study, comprising 24 cases in the de novo lesion group and 20 cases in the ISR group. The mean patient age was 73.4±7.7years, with approximately one-third presenting with concomitant chronic coronary artery disease or cerebrovascular disease. Around one-third of the patients exhibited foot ulcers or gangrene, with a mean lesion length of 239.09±120.09 mm. In the de novo lesion group, 79.2% of lesions were classified as chronic total occlusions (CTOs), whereas 75% of lesions in the ISR group were categorized as Tosaka III. For such complex lesions, the technical success rates were 100% in both groups. The primary patency rates for the de novo group were 86.9% at 12 months and 64.3% at 24 months, compared to 77.0% and 56.5% in the ISR group. Freedom from target lesion revascularization (TLR) rates in the de novo group were 95.8% and 85.4% at 12 and 24 months, respectively, while the ISR group achieved rates of 88.9% and 76.6%. Despite lower primary patency and freedom from target lesion revascularization rates in the ISR group, the differences were not statistically significant (P=0.74).Major adverse events were observed in 12.5% of patients in the de novo group and 35% in the ISR group, with no statistically significant difference (P=0.27).For CLTI patients with complex lesions, including extensive occlusions and severe calcification, the combination of ELA and DCB demonstrates high technical success and favorable safety profiles for both de novo and ISR lesions. Mid-term outcomes indicate a potential trend toward better efficacy in treating de novo lesions compared to ISR lesions.Copyright © 2025. Published by Elsevier Inc.