The effectiveness of antithrombotic drugs for treating sepsis is controversial. Here, we explore the association between antithrombotic therapy and intensive care unit (ICU) mortality for septic patients with peripheral vascular disease.This retrospective cohort study uses data from the Medical Information Mart for Intensive Care (MIMIC)-III database. Kaplan-Meier survival analyses were used to examine mortality among different groups. Cox regression and marginal structural Cox models (MSCMs) were used to adjust for confounding factors. Main Results. The final cohort from the MIMIC-III database included 776 patients, of which 701 survived and 75 perished. The anticoagulant (AC) group and the antiplatelet-anticoagulation (AC-AP) group survived better than the group without antithrombotic treatment (non-AT). The AC and AC-AP groups showed a 0.363-fold and 0.373-fold risk of ICU mortality, respectively, compared with the non-AT group when controlling for age, gender, CRRT, alcohol, heart failure, hypertension, diabetes, obesity, renal failure, liver disease, INR, PT, PPT, and SpO2. Antiplatelet therapy did not reduce ICU mortality. The same trends were apparent from the MSCM. In addition, the AC-AP group exhibited a lower risk of bleeding complications.Although the antithrombotic group (AC and AC-AP groups) demonstrated a higher sequential organ failure assessment (SOFA) score than the group without antithrombotic treatment (non-AT group), the risk of ICU mortality was lower without increasing the risk of bleeding complications. Our study further suggested that anticoagulation therapy may benefit the prognosis of septic patients with peripheral vascular disease.Copyright © 2022 Shiqi Yuan et al.