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The aim of this study was to identify the most effective regimen of multiple doses of oral tranexamic acid (TXA) in achieving maximum reduction of blood loss in total knee arthroplasty (TKA).In this randomized controlled trial, 200 patients were randomized to receive a single dose of 2.0 g of TXA orally two hours preoperatively (group A), a single dose of TXA followed by 1.0 g orally three hours postoperatively (group B), a single dose of TXA followed by 1.0 g three and nine hours postoperatively (group C), or a single dose of TXA followed by 1.0 g orally three, nine, and 15 hours postoperatively (group D). All patients followed a routine enhanced-recovery protocol. The primary outcome measure was the total blood loss. Secondary outcome measures were hidden blood loss (HBL), reduction in the level of haemoglobin, the rate of transfusion and adverse events.Groups C (661.1 ml, SD 262.4) and D (597.7 ml, SD 219.6) had significantly lower mean total blood loss compared with groups A and B. The mean HBL was significantly lower in groups B (699.2 ml), C (533.1 ml) and D (469.9 ml) than in group A (p = 0.006, p < 0.001, and p < 0.001, respectively). Groups C (2.22 ml, SD 0.91) and D (2.04 ml, SD 0.95) had a lower reduction in the level of haemoglobin than groups A and B. However, there were no differences between groups C and D in relation to the three parameters.The addition of two or three postoperative doses of TXA to one preoperative dose produced a significant reduction in blood loss. The two-dose postoperative regimen is the least necessary regimen for clinical efficacy in primary unilateral TKA. The three-dose regimen produced maximum reduction of blood loss.Cite this article:Bone Joint J2018;100-B:1025–32.