Background: We aimed to investigate the effects of antithrombin III administration on the prognosis of severe trauma patients with disseminated intravascular coagulation (DIC). Methods: Medical records of a total of 4023 patients who were admitted to the intensive care unit (ICU) at the single regional trauma center from January 2016 to December 2020 were retrospectively analyzed. After the exclusion of young patients (<15 years old), mild trauma (ISS < 16), non DIC, etc., a total of 140 patients were included in the study. These patients were classified into antithrombin III-administered and non-antithrombin III-administered groups. Clinical data, including laboratory findings, trauma- and ICU-related severity scores, prognosis (including length of hospital stay), and need for organ support, were retrospectively collected. We evaluated the characteristics of the two groups, and compared and analyzed the vital signs, laboratory findings, prognosis, and clinical outcomes of each group. With this, we analyzed the effect of antithrombin III administration in severe trauma patients with DIC. Results: Of the 140 patients, 61 were treated with antithrombin III. No significant difference was observed in the baseline characteristics between the two groups for initial laboratory results, initial vital signs, or trauma-related severity scores. The improvement of the sequential organ failure assessment (SOFA) score, a prognostic marker, was significantly greater in the administered group (p= 0.009). Additionally, the antithrombin-administered group showed a larger improvement in the SOFA score than the non-administered group (p= 0.002). However, there was no statistical difference between the two groups for the frequency or duration of organ support treatments (renal replacement therapy, mechanical ventilation), mortality, or length of hospital stay. Conclusion: Antithrombin III administration in severe trauma patients with DIC improved SOFA scores and aided in multi-organ dysfunction recovery. Appropriate indications should be studied to maximize the drug’s improvement effect in patients with severe trauma in the future.