Disseminated intravascular coagulation (DIC) is a lethal complication in patients with hematologic malignancies (HMs). DIC can be induced by the HM itself, but also by HM-associated secondary infection; however, whether difference of triggering factor impacts the outcome of DIC in HM patients remains unknown. The objective of this study is to clarify the difference between HM-induced DIC and infection-induced DIC in HM patients regarding treatment response and prognosis. HM-induced DIC (158 episodes) and infection-induced DIC in HM patients (83 episodes) from a single center were retrospectively analyzed. Recombinant human thrombomodulin (rhTM) was administered in 149 episodes, while the remaining received conventional therapies. In HM-induced DIC, improvement by day 7 was 46% (95% confidence interval CI, 38–54), and rhTM enhanced the improvement (hazard ratio HR, 1.7; 95% CI, 1.1–2.4). In contrast, improvement of infection-induced DIC was significantly worse (29%; 95% CI, 20–39 on day 7), and this was not influenced by rhTM (HR, 1.0; 95% CI, 0.50–2.2). Thirty-day survival in HM-induced DIC and infection-induced DIC was 87% (95% CI, 81–92) and 53% (95% CI, 42–63), respectively, and was not affected by treatment. A DIC score (Japanese Ministry of Health and Welfare criteria) of ≥5 was a predictor of worse survival in both types of DIC (HR, 2.5; 95% CI, 1.5–3.9). This study showed the inadequacy of current therapeutic strategies for secondary infection-induced DIC, the prognosis of which was significantly worse than HM-induced DIC, and the limited efficacy of rhTM only in the improvement of HM-induced DIC. •Triggering factors of DIC in hematological malignancy (HM) had impact on the outcome.•Survival rate of infection-induced DIC in HM was almost half that of HM-induced DIC.•Recombinant human thrombomodulin (rhTM) enhanced recovery only from HM-induced DIC.•Difference of the survival according to the treatment modalities was not observed.