The antifibrinolytic tranexamic acid reduces surgical blood loss, but studies have not identified an optimal regimen. We studied different dosages, timings, and modes of administration to identify the most effective regimen of tranexamic acid in achieving maximum reduction of blood loss in TKA. We prospectively studied five regimens (four intravenous, one local; 40 patients each) with a control group (no tranexamic acid). The four intravenous (10-mg/kg dose) regimens included (1) intraoperative dose (IO) given before tourniquet deflation, (2) additional preoperative dose (POIO), (3) additional postoperative dose (IOPO), and (4) all three doses (POIOPO). The fifth regimen was a single local application (LA). Two independent parameters of drain loss and total blood loss, calculated by the hemoglobin balance method, were evaluated statistically. Both parameters were reduced in all five regimens as against the control. A significant reduction in drain loss was seen in the POIO, IOPO, and POIOPO groups whereas total blood loss was significantly reduced in the POIO, POIOPO, and LA groups. The POIOPO group had the least drain loss (303 mL) and least total blood loss (688 mL). The IO group had the greatest drain loss and the IOPO group the greatest total blood loss. Single-dose tranexamic acid did not give effective results. The two-dose regimen of POIO was the least amount necessary for effective results. When compared against the control, this regimen produced reduction of drain loss and total blood loss, whereas the IOPO regimen did not. The three-dose regimen of POIOPO produced maximum effective reduction of drain loss and total blood loss.