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Tourniquet use during primary total knee arthroplasty is thought to reduce intraoperative blood loss and improve visibility. Our goal was to investigate whether tourniquet use is necessary for controlling intraoperative blood loss when alternatives such as tranexamic acid (TXA) are available.One hundred and fifty patients were equally randomized to 3 groups. Group A was treated with a tourniquet as well as multiple doses of intravenous TXA (20 mg/kg 5 to 10 minutes before the skin incision and 10 mg/kg 3, 6, 12, and 24 hours later) along with 1 g of topical TXA, Group B was treated the same as Group A but without the tourniquet, and Group C was treated with the tourniquet only.The amount of intraoperative blood loss was similar for the 3 groups. Group B had significantly less hidden blood loss than Group A (p = 0.018) and Group C (p < 0.001). No significant differences (p > 0.05) were observed between Group A and Group B with regard to total blood loss, drainage volume, intraoperative blood loss, transfusion rate, or maximum change in the hemoglobin (Hb) level. We also found significantly more benefits for Group B compared with Groups A and C with regard to postoperative swelling ratio, levels of inflammatory biomarkers, visual analog scale (VAS) pain scores, range of motion at discharge, Hospital for Special Surgery (HSS) score, and patient satisfaction. There were no significant differences (p > 0.05) in the deep venous thrombosis or pulmonary embolus rates among the 3 groups. More wound secretion was observed in the groups in which a tourniquet was used.Patients treated with multiple doses of intravenous and topical TXA without a tourniquet had less hidden blood loss, a lower ratio of postoperative knee swelling, less postoperative knee pain, lower levels of inflammatory biomarkers, better early knee function, and even better early satisfaction than those treated with a tourniquet. Long-term follow-up should be performed to evaluate the effects on prosthetic fixation and long-term survival of total knee arthroplasty performed without a tourniquet.Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.