Multiple studies have shown tranexamic acid (TXA) to reduce blood loss and transfusion rates in patients undergoing total knee arthroplasty (TKA). Accordingly, TXA has become a routine blood conservation agent for TKA. In contrast, ε-aminocaproic acid (EACA), a similar acting antifibrinolytic to TXA, has been less frequently used. This study evaluated whether EACA is as efficacious as TXA in reducing postoperative blood transfusion rates and compared the cost per surgery between agents. A multicenter retrospective chart review of elective unilateral TKA from April 2012 through December 2014 was performed. Five hospitals within a health care system participated. Data collected included age, gender, severity of illness score, use of antifibrinolytic and dose, red blood cell (RBC) transfusions and the number of units, and preadmission and discharge hemoglobin (Hb). Dosing of the antifibrinolytic differed based on the agent used, 5 or 10 g (based on weight) for EACA versus 1 g for TXA. The institutional acquisition cost of each antifibrinolytic was obtained and averaged over the study period. Of 2,922 primary unilateral TKA cases, 820 patients received EACA, 610 patients received TXA, and 1,492 patients received no antifibrinolytic (control group). Compared with the control group both EACA and TXA groups had significantly fewer patients transfused (EACA 2.8% [p < 0.0001], TXA 3.2% [p < 0.0001] vs. control 10.8%) and lower mean RBC units transfused per patient (EACA 0.05 units/patient [pt] [p < 0.0001], TXA 0.05 units/pt [p < 0.0001] vs. control 0.19 units/pt]. There was no difference in mean RBC units transfused per patient, percentage of patients transfused, and discharge Hb levels between the EACA and TXA groups (p = 0.822, 0.236, and 0.322, respectively). Medication acquisition cost for EACA averaged $2.23 per surgery compared with TXA at $39.58 per surgery. Administration of EACA or TXA significantly decreased postoperative transfusion rates compared with no antifibrinolytic therapy. Utilization of EACA for unilateral TKA proved to be comparable to TXA in all studied aspects at a lower cost. The level of evidence for the study is Level 3.