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Epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) are synthetic amino acid derivatives that interfere with fibrinolysis, promoting hemostasis by pharmacological means. Although both drugs have been shown to decrease blood loss with a minimal risk of thromboembolic adverse events following cardiac and vascular surgery, we are aware of only 1 published trial that directly compared the antifibrinolytic effects of EACA with those of TXA after total knee arthroplasty (TKA). The primary aim of this prospective, randomized, controlled trial was to determine whether TXA provides superior blood conservation following TKA compared with that provided by EACA.A total of 194 patients scheduled to undergo a primary unilateral TKA in the same community-based hospital were prospectively randomized to receive intravenous EACA (n = 96) or TXA (n = 98). Both the patients and the operating surgeons were blinded to the treatment assignments. Primary outcome measures included transfusions, estimated blood loss, and the drop in the hemoglobin (Hgb) level. Secondary outcomes measures included the change in the serum creatinine level, postoperative complications, and length of hospital stay.Although the patients who received TXA averaged less estimated blood loss than the patients who received EACA (t185 = 2.18, p = 0.031; mean difference = 144.2 mL, 95% confidence interval = 13.62 to 274.78 mL), no transfusions were required in either group. We observed no statistically significant or clinically relevant between-group differences in the change in Hgb or serum creatinine level, postoperative complications, or length of hospital stay.Although the estimated blood loss was significantly greater in the EACA group, no transfusions were required and no significant between-group differences were observed for any other outcomes measured. We concluded that EACA may be an acceptable alternative to TXA for blood conservation following TKA, although replication of our results in noninferiority trials is necessary.Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.