Abstract Objective The aim of this study was to report the primary outcomes of a pilot study investigating the safety and efficacy of sirolimus drug-coated balloons (SELUTION) for endovascular postatherectomy treatment of native occluded femoropopliteal lesions in patients with chronic limb-threatening ischemia (CLTI). Materials and Methods This study analyzes a cohort of CLTI patients with femoropopliteal artery occlusions treated with combined rotational atherectomy and postatherectomy angioplasty using the SELUTION device. The primary outcome measures were amputation-free survival (AFS) defined as time to major limb (above ankle) amputation of the index leg or death from any cause. Secondary outcome measures included technical success, overall survival, major amputation of the index leg, major adverse limb event (MALE) defined as major amputation or any further major revascularization intervention of the treated segment during the follow-up period and primary patency at 12 months. Results Between April 2021 and January 2022, nine patients (mean age: 64.0 ± 8.4, 66.7% male) with femoropopliteal occlusive lesions (mean lesion length: 141.1mm, range: 40–400) were treated with the above-combined approach. Technical success was 100%. At 12 months, the AFS was 88.9%, with one death and zero major amputations (88.9% survival and 100% limb salvage, respectively); only two patients (22.2%) suffered a MALE; primary patency was 75%. No adverse events related to the sirolimus drug-coated balloon nor to the atherectomy device were observed. Conclusion Combining sirolimus drug-coated balloon and atherectomy for treatment of femoropopliteal occlusions in CLTI patients is a safe and effective approach achieving satisfactory patency and adverse event rates.