Abstract Background The etiology of acute limb ischemia (ALI) involves embolism as well as atherosclerotic thrombosis. Although endovascular therapy (EVT) or Fogarty thrombectomy (Fogarty TE) is the recommended revascularization method for ALI, treatment choice based on patient characteristics remains controversial. Purpose This study aimed to evaluate the differences in clinical outcomes between primary treatments and identify predictive factors affecting clinical outcomes in patients with ALI. Methods This retrospective study used data from the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC) database, from April 2012 to March 2020. We analyzed 18,701 patients with ALI and categorized them into medication and invasive treatment groups (EVT alone, Fogarty TE alone, bypass surgery alone, and hybrid treatment). The EVT-alone and Fogarty TE-alone groups were compared after propensity score matching, considering 19 clinically relevant covariates. The primary outcomes were in-hospital mortality, major amputation, and bleeding complications (anemia requiring transfusion or endoscopic hemostasis). The secondary outcomes were major adverse cardiovascular events (myocardial infarction, coronary intervention, heart failure, stroke, and cerebral hemorrhage), major amputation and/or death, hospitalization duration, and total cost during hospitalization. Results The EVT-alone group had more patients at a higher risk of atherosclerotic disease, including peripheral artery disease (PAD), chronic kidney disease (CKD), or hemodialysis. The Fogarty TE-alone group had more patients at a higher risk of embolism, including AF or AFL. After propensity score matching, in-hospital mortality (odds ratio [OR]: 1.58, 95% confidence interval [CI]: 1.29–1.92, p<.0001), bleeding complications (OR: 1.28, 95% CI: 1.12–1.46, p=0.0002), and major amputation rates (OR: 1.44, 95% CI: 1.17–1.76, p=0.0004) were significantly higher in the EVT-alone group than in the Fogarty TE-alone group. Major amputation and/or death rates and total hospitalization costs were higher in the EVT-alone group than in the Fogarty TE-alone group. In interaction analyses, EVT demonstrated a favorable trend of lower risks of death and/or major amputation in patients with PAD, CKD, and diabetes mellitus (all risk factors for atherosclerotic disease), especially in those with PAD and CKD. Conclusions Fogarty TE may be the preferred primary treatment for patients with ALI, particularly those without PAD or CKD.Study flowchartForest plot analyzing interaction effect