Objective: Immune reactions following traumatic brain injury (TBI) cause many complications, including intravascular dissemination. Antithrombin III (AT-III) plays an important role in suppressing abnormal clot formation and ensuring hemostasis. Therefore, we investigated the efficacy of serum AT-III in patients with severe TBI. Methods: This retrospective study included 224 patients with severe TBI who visited a single regional trauma center between 2018 and 2020. AT-III levels were measured immediately after the TBI diagnosis. AT-III deficiency was defined as an AT-III serum level <70%. Patient characteristics, injury severity, and procedures were also investigated. Patient outcomes included Glasgow Outcome Scale scores at discharge and mortality. Results: AT-III levels were significantly lower in the AT-III deficient group (n=89; 48.27% ± 1.91%) than in the AT-III sufficient group (n = 135, 78.90% ± 1.52%) (p < 0.001). Mortality occurred in 72 of the 224 patients (33.04%), indicating that there were significantly more patients in the AT-III-deficient group (45/89, 50.6%) than in the AT-III-sufficient group (27/135, 20%). Significant risk factors for mortality included the Glasgow Coma Scale score (P = 0.003), pupil dilatation (P = 0.031), disseminated intravascular coagulopathy (P = 0.012), serum AT-III level (P = 0.033), and procedures including barbiturate coma therapy (P = 0.010). Serum AT-III levels were significantly correlated with Glasgow Outcome Scale scores at discharge (correlation coefficient = 0.455, p < 0.001). Conclusion Patients with AT-III deficiency after severe TBI may require more intensive care during treatment, because AT-III levels reflect injury severity and correlate with mortality.