A retrospective study was conducted to evaluate the need for perioperative autotransfusions and the amount of blood loss by comparing patients receiving different tranexamic acid (TXA) regimens following total joint replacement (TJR). A total of 1675 patients undergoing TJR were included: 76 did not receive TXA administration (group A); 77 received IV TXA (group B); 1510 received IV followed by IA administration of TXA (group C); and 12 received IA TXA administration alone (group D). Significant between-group differences were observed in intraoperative and postoperative blood loss (p<0.05). Blood autotransfusion and allogeneic transfusion rates were significantly higher in group D compared with the other treatment strategies (p<0.001) and with the control group of patients who did not receive TXA (p<0.05). IV combined with IA TXA administration represents the most effective way to prevent blood loss following TJA surgery. Conversely, isolated IA administration of TXA did not reduce the need for postoperative transfusions.