Background Endovascular treatment (EVT) is recommended for superficial femoral artery (SFA) lesions, and good results have been reported after implantation of drug-eluting stents (DES) for SFA. However, the major concern after implantation is acute thrombosis during the follow-up period, resulting in major amputation and major adverse limb events. In this study, we examined the incidence and outcome of acute thrombosis after DES implantation in the SFA. Objectives and Methods DES implantation for a femoropopliteal lesion was performed in 288 patients at multiple centers in Japan from 2019 to 2021. A total of 25 patients (8.6%) with DES acute occlusion were analyzed retrospectively. The primary endpoint was amputation-free survival (AFS) after acute occlusion. Results The median patient age was 77 years, with 48% having diabetes, 40% undergoing maintenance dialysis, and 66% having chronic limb-threatening ischemia (CLTI). The mean time from initial DES implantation to acute occlusion was 153.5 ± 177.6 days, with a median of 104 days. EVT was performed in 18 patients (72%), surgical revascularization in 3 (12%), and conservative treatment in 4 (16%). Two deaths within 30 days were both due to sepsis. No major amputation or major adverse cardiovascular events occurred within 30 days. The 1-year rates of patency and freedom from target lesion revascularization after DES thrombosis were 22.9% and 48.8%, respectively. AFS at 1 year was 55.1%. Conclusion Acute DES occlusion is relatively frequent, and the outcome is poor. Therefore, the indication of DES implantation for a complex SFA lesion may require careful consideration. Further investigation may be needed in DES implantation for a complex SFA lesion.