Background: This study aims to assess the effectiveness and identify the risk factors associated with postoperative restenosis in patients with femoropopliteal in-stent restenosis (FP-ISR) disease treated with excimer laser ablation (ELA) combined with drug-coated balloon (DCB) versus DCB alone. Methods: This retrospective real-world study compares patients with FP-ISR treated with ELA + DCB versus DCB alone. Additionally, subgroup analysis was conducted for long-segment lesions (lesion length >= 200 mm) and Tosaka III lesions. Then Cox regression analysis was used to examine 24-month outcomes of target lesion revascularization and restenosis. Results: We found no significant differences in primary patency and freedom from clinically driven target lesion revascularization (CD-TLR) at 24 months between the ELA + DCB group (49 patients) and the DCB group (82 patients). In the subgroup analysis of long-segment lesions (target lesion length >= 200 mm), the results showed that ELA + DCB was superior to DCB at 24 months in terms of both primary patency (55.0% vs 35.3%; P = 0.048) and freedom from CD-TLR (77.8% vs 50.8%; P = 0.033). The 2 treatment methods did not show statistical significance in the subgroup analysis of Tosaka III patients. Target lesion length of >= 200 mm was found to have a significant association with restenosis (hazard ratio = 5.28; 95% CI, 2.48-11.23; P < 0.001) and freedom from CD-TLR (hazard ratio = 3.02; 95% CI, 1.02-9.30; P = 0.044) in the multivariate analysis. Conclusions: We do not have sufficient evidence to show a significant difference between ELA + DCB and DCB alone for FP-ISR. However, for patients with long-segment FP-ISR lesions, ELA + DCB may provide better long-term patency.