OBJECTIVE: The mechanisms linking severe inflammation and coagulation during heatstroke are poorly understood. Here, we examined the roles of the tissue factor pathway, leukocyte activation, and mediators of innate immunity in patients admitted to an intensive care unit for heatstroke during an intense heat wave in Paris. DESIGN: Retrospective observational study. SETTING: Intensive care unit of a university medical center. PATIENTS: Eighteen critically ill severe patients with heatstroke were enrolled in the study and 14 age-matched patients with severe sepsis as controls. INTERVENTIONS: None. MEASUREMENTS and MAIN RESULTS: High circulating levels of some inflammation and stress mediators (interleukin-6, -8, C5a, interleukin-1 receptor antagonist, heat shock protein 60 and 70) were observed. Blood leukocyte activation was shown by beta2 integrin up-regulation, L-selectin down-regulation, and strong production of reactive oxygen species and interleukin-8 ex vivo. High levels of circulating promatrix metalloproteinase-9 were detected in all the patients studied, and its active form was present in two patients. Overt disseminated intravascular coagulation according to the International Society of Thrombosis and Hemostasis score was present in five patients. Whole-blood tissue factor was present in all the patients and part of this activity was associated with microparticles in five patients. The degrees of inflammation and disseminated intravascular coagulation are correlated with clinical severity. CONCLUSIONS: These results suggest that neutrophil activation plays a key role in the acute activation of coagulation observed during severe heatstroke, despite a rapid and sustained antiinflammatory response. The comparison with a group of patients with severe sepsis suggests some common mechanisms, but more intense responses during heatstroke.