Abstract Background Cholinesterase (ChE) has been used to be an indicator of the protein synthesis ability in the liver and nutritional status. Recent findings have identified low ChE levels as a prognostic factor for heart failure. However, the relationship between serum ChE levels and clinical outcomes in patients with lower extremity artery disease (LEAD) undergoing endovascular treatment (EVT) remains unclear. Purpose This study aimed to investigate the association between pre-procedure serum ChE levels and clinical outcomes in LEAD patients undergoing EVT. Methods The subjects were 283 consecutive LEAD patients who underwent EVT at our University Hospital were included. The primary outcome measure was the cumulative incidence of major adverse cardiovascular events (MACEs) within two years, defined as the composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke. Results The mean age of the cohort was 72.6±10.6 years, with 67.5% being male. Within two years, 45 patients experienced MACE, and Kaplan-Meier curves demonstrated the cumulative incidence of MACE within two years was 19.3%. Receiver operating characteristic curve analysis showed that serum ChE was a univariable factor that predicted MACE within two years with moderate accuracy (area under the curve = 0.693, 95% confidence interval (CI) 0.615–0.771), with an optimal serum ChE cutoff level of 284 units/L. According to the optimal cut-off value, patients were divided into low ChE (ChE ≤ 284 units/L, N=189) and high ChE ((ChE > 284 units/L, N=94) groups. In the baseline characteristics between the two groups, age was significantly higher in the low ChE groups than in the high ChE group. There were no significant differences in gender, the prevalence of diabetes mellitus, hypertension, and the proportions of previous stroke, and previous myocardial infarction between the two groups. In contrast, the proportions of hemodialysis (HD) and chronic limb-threatening ischemia (CLTI) were higher in the low ChE groups. Kaplan-Meier curves demonstrated a significantly higher cumulative incidence of MACE in the low ChE group compared to the high ChE group (log-rank p < 0.001). In multivariate analysis using Cox proportional hazards models adjusting for risk factors, including HD and CLTI, low ChE group was independently associated with MACE (low ChE group: hazard ratio (HR) 4.24, 95% confidence interval (CI) 1.24-14.49, p=0.021). In addition, Cox proportional hazards models using serum ChE level and HD revealed that patients with both low-ChE and HD showed a greater risk of MACE (HR 15.19; 95% CI 3.60–64.02; P < 0.001) after EVT as compared to patients with neither low-CHE nor HD. Conclusions In LEAD patients undergoing EVT, lower ChE levels were independently associated with a higher risk of MACE, regardless of HD. Assessment of serum ChE level may provide insights into identifying high-risk LEAD patients who need careful attention after EVT.