Thrombin is the central coagulation protease that activates clotting proteins, triggers platelet aggregation, and converts fibrinogen to fibrin. Relationships between thrombin generation (TG) and clinical outcomes have not been defined following trauma. We hypothesize that TG is predictive of transfusion requirements and patient outcomes. Plasma was collected from 406 highest-level activation trauma patients upon admission and 29 healthy donors. Standard coagulation tests were performed, and TG was measured by calibrated automated thrombogram. Mann-Whitney U-tests were used to compare healthy versus trauma patients, and subgroup analyses were used to compare hypocoagulable versus nonhypocoagulable patients. Hypocoagulability was determined by area under the receiver operating characteristic curve analysis and was defined as peak TG of less than 250 nM. Multiple logistic regressions were used to assess the ability of TG to predict massive transfusion and mortality. The median (interquartile range) age was 39 years (28-52 years), with an Injury Severity Score (ISS) of 17 (9-26). The trauma patients had greater TG (peak, 316.2 nM 270.1-355.5 nM) compared with the healthy controls (124.6 nM 91.1-156.2 nM), p < 0.001. The overall rate of hypocoagulability was 17%. The patients with peak TG of less than 250 nM were more severely injured (ISS, 25 13-30 vs. 16 9-25, p = 0.003); required more transfusions of red blood cells (p = 0.02), plasma (p = 0.003), and platelets (p = 0.006); had fewer hospital-free days (p = 0.001); and had increased mortality (10% vs. 3% at 24 hours, p = 0.006, and 29% vs. 11% at 30 days, p = 0.0004). Peak TG of less than 250 nM was predictive of massive transfusion (odds ratio, 4.18; p = 0.01) and 30-day mortality (odds ratio, 2.78; p = 0.02). Finally, peak TG was inversely correlated with standard coagulation tests. While the physiologic response to injury is to upregulate plasma procoagulant activity, the patients with reduced TG required more transfusions and had poorer outcomes. Measuring TG may provide an exquisitely sensitive tool for detecting disturbances in the enzymatic phases of coagulation in critically injured patients. Prognostic/epidemiologic study, level III.