The application of a pneumatic tourniquet in orthopedic procedures enhances local fibrinolysis. Consequently, a short-term antifibrinolytic therapy may be indicated in this clinical situation to reduce postoperative blood loss. The purpose of this prospective double-blind study was to investigate the effect of tranexamic acid (TA) on blood loss associated with total knee arthroplasty (TKA). Seventy-five patients scheduled for 77 TKAs were randomized to receive either TA (n = 39) or equal volume of normal saline (NS, n = 38). Before deflation of the tourniquet, 15 mg/kg of TA was given intravenously followed by two 10-mg/kg additional doses. Perioperative blood loss gathered in surgical gauzes, suction reservoirs, and postoperative drainage system was measured. The number of transfusions given during hospitalization was registered. Total blood loss (mean +/- SD) was 689 +/- 289 mL in the TA group and 1509 +/- 643 mL in the NS group (P < 0.0001). The mean number of transfused red cell units in the TA group was 1.0 +/- 1.2 compared to 3.1 +/- 1.6 in the NS group (P < 0.0001). Twenty-two patients in the TA group and four patients in the NS group were treated without transfusion (P < 0.00003). Two patients in the TA group and three in the NS group had a deep venous thrombosis, including a fatal case of pulmonary embolism in the NS group. We conclude that short-term TA therapy significantly reduces TKA-associated blood loss and transfusion requirements without increasing thromboembolic complications.