Septic patients can develop disseminated intravascular coagulation (DIC), which is characterized by systemic blood coagulation and an increased risk of life-threatening haemorrhage. Although antithrombin (AT) and thrombomodulin (TM) combination anticoagulant therapy is frequently used to treat septic patients with DIC in Japan, its effectiveness in improving patient outcomes remains unclear. In this large-scale multicentre retrospective study of adult septic patients with DIC treated at Japanese hospitals between February 2010 and March 2016, we compared in-hospital mortality between AT monotherapy and AT + TM combination therapy. We performed logistic regression analysis with in-hospital mortality as the dependent variable and anticoagulant therapy as the main independent variable of interest. Covariates included patient demographics, disease severity, and body surface area. The AT group and AT + TM group comprised 1,017 patients from 352 hospitals and 1,205 patients from 349 hospitals, respectively. AT + TM combination therapy was not significantly associated with lower mortality when compared with AT monotherapy (odds ratio: 0.97, 95% confidence interval: 0.78-1.21; P = 0.81). AT + TM combination therapy was also not superior to AT monotherapy in reducing mechanical ventilation or hospitalization durations. Despite its widespread use for treating sepsis with DIC, AT + TM combination therapy is not more effective in improving prognoses than the simpler AT monotherapy.