To determine the relationship between macrophage migration inhibitory factor (MIF) and disseminated intravascular coagulation (DIC) in patients with systemic inflammatory response syndrome (SIRS) and sepsis, and their relationship to multiple organ dysfunction syndrome (MODS) and prognosis, we conducted a prospective cohort study. Forty-eight patients with SIRS or sepsis were classified as 20 DIC and 28 non-DIC patients. MIF, tumor necrosis factor-alpha (TNF-alpha), soluble fibrin, protein C activity (protein C), and plasminogen activator inhibitor-1 (PAI-1) were all measured within 24 h after the patients met the criteria of SIRS or sepsis (day 0), and on days 1 to 4. The number of SIRS criteria that the patients met and the DIC scores were determined simultaneously. In DIC patients, significantly higher levels of MIF, TNF-alpha, soluble fibrin, PAI-1 were found compared with non-DIC patients. We also found significantly lower protein C levels in the DIC patients than in the non-DIC patients. Significant correlations were found between the peak levels of MIF and soluble fibrin in the DIC patients (rs = 0.496, p < 0.0407). All DIC patients had MODS and also showed a higher number of dysfunctioning organs and a poorer prognosis than the non-DIC patients. A simple logistic regression analysis showed the peak MIF levels and DIC significantly to be related to the patients' death (odds ratio 1.016 and 40.5; p < 0.0409, p < 0.0009, respectively). In conclusion, DIC patients with elevated levels of MIF and TNF-alpha had more organ dysfunctions leading to a poor prognosis in a population of SIRS and sepsis patients. MIF may therefore play a role in the inflammatory and thrombotic processes in DIC patients.