Sepsis induces alterations of coagulation suggesting both hypercoagulable or hypocoagulable features. The result of their combination remains unknown, making it difficult to predict whether one prevails over the other. Thrombin generation tests (TGTs) stand as an interesting tool to establish an integrative phenotype of coagulation. It has been reported that septic patients display a hypocoagulable trait using TGT. However, protein C (PC) system response was not evaluated. We aimed at describing the thrombin generation profile in patients with septic shock under conditions that are sensitive to PC system to evaluate the net results of coagulation abnormalities and to determine whether hypercoagulable or hypocoagulable traits coexist within a given individual. Thrombin generation was studied in plasma from patients presenting with septic shock at diagnosis and 6 h after a conventional therapeutic management using calibrated automated thrombography with or without thrombomodulin (TM) addition. Patients exhibit clear alterations of TGT that present as both consumption-related hypocoagulability (evidenced without TM addition) but also hypercoagulability by decreased sensitivity to the PC system evidenced with TM addition. No difference could be demonstrated between survivors and nonsurvivors at Day 28, but patients who do not respond to therapeutics at 6 h seem to be more hypercoagulable. More importantly, if our results evidence heterogeneity between patients, we show that alterations of coagulation result in an equilibrium in the majority of patients, thus suggesting "normocoagulability"; but, in the presence of a biological imbalance between baseline thrombin generation and sensitivity to TM, the global effect mostly tends toward hypercoagulability. Thus, TGT may help identify distinct biological coagulation phenotypes in the complex alterations induced by sepsis.