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We evaluated the efficacy of the prophylactic administration of ε-aminocaproic acid and tranexamic acid for reducing blood product requirements in orthotopic liver transplantation (OLT) in a prospective, double-blinded study performed in 132 consecutive patients. Patients were randomized to three groups and given one of three drugs prophylactically: tranexamic acid, 10 mg · kg−1 · h−1; ε-aminocaproic acid, 16 mg · kg−1 · h−1, and placebo (isotonic saline). Perioperative management was standardized. Coagulation tests, thromboelastogram, and blood requirements were recorded during OLT and in the first 24 h. There were no differences in diagnosis, Child score, or preoperative coagulation tests among groups. Administration of packed red blood cells was significantly reduced (P = 0.023) during OLT in the tranexamic acid group, but not in the ε-aminocaproic acid group. There were no differences in transfusion requirements after OLT. Thromboembolic events, reoperations, and mortality were similar in the three groups. Prophylactic administration of tranexamic acid, but not ε-aminocaproic acid, significantly reduces total packed red blood cell usage during OLT.In a randomized study of 132 consecutive patients undergoing liver transplantation, we found that tranexamic acid, but not ε-aminocaproic acid, reduced intraoperative total packed red blood cell transfusion.