Background and Aims Stenting and plain old balloon angioplasty (POBA) remain the primary treatments for femoropopliteal in-stent restenosis (ISR). These approaches demonstrate good short-term patency; however, ISR frequently recurs due to continuous stimulation of the vascular intima by the stent. With advancements in endovascular technology, excimer laser ablation (ELA) combined with drug-coated balloons (DCB) offers a novel strategy for treating ISR. This study investigated the safety and efficacy of ELA combined with DCB for complex femoropopliteal ISR.Methods The clinical data of 69 patients with femoropopliteal ISR treated with interventional procedures between June 2020 and June 2022 were retrospectively analyzed. Among them, 27 patients underwent ELA combined with DCB treatment (ELA+DCB group), and 42 patients underwent POBA combined with DCB treatment (POBA+DCB group). Relevant clinical variables were compared between the two groups.Results No significant differences were observed in baseline characteristics between the two groups (all P>0.05). True lumen re-entry was achieved in all 69 patients. The procedural success rates for the ELA+DCB and POBA+DCB groups were 92.6% (25/27) and 90.5% (38/42), respectively, with no statistically significant difference (P>0.05). Intraoperative adverse events were comparable between groups (all P>0.05). Logistic regression analysis indicated that thrombus in the target lesion was an independent risk factor for distal embolization during ELA+DCB (HR=24.695, 95% CI=1.061-574.904, P=0.046). Ankle-brachial index (ABI) values immediately after the procedure and at 1 and 6 months postoperatively showed no significant differences between the two groups (all P>0.05). However, the ELA+DCB group demonstrated superior ABI outcomes at 12, 18, and 24 months postoperatively (all P<0.05). There were no significant differences in all-cause mortality or amputation rates postoperatively (both P>0.05). Kaplan-Meier analysis showed that the ELA+DCB group had higher 2-year freedom from target lesion revascularization (81.5% vs. 57.1%, P=0.044) and 2-year patency rates (77.8% vs. 52.4%, P=0.031) compared to the POBA+DCB group. ROC curve analysis identified a laser tube diameter/reference vessel diameter (TD/RVD) ratio cutoff value of 0.47 (AUC=0.825, 95% CI=0.619-1.000) for predicting 2-year patency after ELA plus DCB treatment, with a specificity of 66.7%. Cox regression analysis revealed that postoperative antithrombotic therapy (HR=0.033, 95% CI=0.002-0.661, P=0.026), ≥2 tibial arteries recanalized (HR=0.022, 95% CI=0.001-0.808, P=0.038), and TD/RVD ≥ 0.47 (HR=0.002, 95% CI=0.000-0.403, P=0.022) were independent factors associated with improved 2-year patency after ELA plus DCB treatment.Conclusion For complex femoropopliteal ISR, ELA combined with DCB does not show significant advantages in safety compared to POBA combined with DCB, but it provides superior long-term efficacy. Intraoperative management and postoperative antithrombotic therapy may influence the mid- to long-term outcomes of ELA combined with DCB for treating complex femoropopliteal ISR.