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Recombinant human thrombomodulin (rhTM) is often used concomitantly with antithrombin (AT) to treat disseminated intravascular coagulation (DIC). This observational study aimed to investigate the efficacy and safety of AT + rhTM combination therapy.One hundred twenty-nine patients with severe sepsis and DIC participated in this study. Of these, 78 patients were treated with AT + rhTM (AT + rhTM group) and 51 patients were treated with AT alone (AT group). We compared coagulation and inflammation markers, Sequential Organ Failure Assessment score, and DIC score at day 0 (baseline) and day 7 between the 2 groups. Bleeding events and 28-day mortality were also compared.Platelet counts and D-dimer levels at day 7 significantly improved in the AT + rhTM group compared with the AT group, and 28-day mortality was significantly lower in the AT + rhTM group than in the AT group (AT + rhTM: 15.4% vs AT: 29.4%). During the study period, the incidence of bleeding complications was similar in both groups (AT + rhTM: 6.4% vs AT: 7.8%).Compared with AT monotherapy, combination therapy with AT and rhTM may be more effective in improving platelet counts and D-dimer levels, as well as reducing mortality, in patients with severe sepsis-associated DIC.