180 patients undergoing total knee arthroplasty were included in this trial to evaluate the effect that timing of tranexamic acid administration has on blood loss. Patients were randomized to receive 30mg/kg of tranexamic acid infused intravenously 15 minutes before tourniquet inflation, 15 min after tourniquet inflation, at tourniquet deflation, or to a control that did not receive tranexamic acid. Total blood loss and transfusion rate were significantly reduced in the group of patients that received tranexamic acid 15 minutes prior to tourniquet inflation compared to the three other groups. Patients who received tranexamic acid 15 minutes after tourniquet inflation or at tourniquet deflation also demonstrated a significant reduction in total blood loss and transfusion rate compared to patients who did not receive tranexamic acid. The results of this study suggest that tranexamic acid infusion prior to tourniquet inflation may provide optimal reductions in blood loss and transfusion rate in patients undergoing total knee arthroplasty.