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Background: Tranexamic acid (TXA) administration after trauma has not been proven to improve survival in the United States. Trauma patients were presented to the hospital with a spectrum of fibrinolytic activity, in which physiological levels of fibrinolysis are associated with the lowest mortality. We hypothesize that trauma patients who present to the hospital with physiological levels of fibrinolysis will have increased mortality if they receive TXA., Materials and Methods: Severely injured trauma patients, followed prospectively from 2014 to 2016, were included in the analysis. The patient's first thrombelastography was used to stratify patients into fibrinolysis phenotypes which included fibrinolysis shutdown, physiological fibrinolysis, and systemic hyperfibrinolysis. The primary outcome was in-hospital mortality., Results: A total of 232 patients were analyzed (11% received TXA) with an overall mortality rate of 20%. TXA administration was associated with a higher new injury severity score (49 versus 28; P = 0.001), massive transfusion rate (69% versus 12%; P < 0.001), and mortality (52% versus 17%; P < 0.001). Hyperfibrinolysis and shutdown had higher mortality rates than physiological group (24% versus 30% versus 14%; P = 0.050). The effect of TXA within phenotypes was not significant for shutdown (28% versus 38%; P = 0.604) but was significant in the physiological group (11% versus 63%; P < 0.001) and systemic hyperfibrinolysis (19% versus 55%; P = 0.023). After adjusting for new injury severity score, TXA remained a significant predictor of mortality for patients with physiological fibrinolysis (P = 0.018)., Conclusions: There was no clear benefit of receiving TXA in this study, and patients who present to the hospital with physiologic levels of fibrinolysis, who received TXA, had the highest mortality. The role of TXA in mature trauma systems remains unclear, and emerging data supports it may have adverse effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)