Tranexamic acid (TXA) is often used to prevent excessive blood loss during bilateral TKA. Although it diminishes blood loss, TXA may have a potentially elevated thrombogenic risk with extra, unnecessary doses of TXA in this high-risk population. To date, the most efficacious dosing protocol in this setting has not yet been ascertained. We compared one versus two doses of intravenous TXA in the setting of same-day bilateral TKA in terms of (1) perioperative blood loss that occurred during the hospital stay, (2) transfusion usage during the hospital stay, and (3) major complications occurring within 30 days of surgery. Between August 2013 and October 2016, 309 patients underwent simultaneous bilateral TKA performed by one of five attending surgeons. During that time, indications for same-day bilateral TKA included bilateral knee pathology in which each knee was independently indicated for TKA and the patient preferred bilateral simultaneous TKAs versus staged bilateral surgeries. Patients who had cardiac disease or an American Society for Anesthesiologists physical classification score of greater than 2 were not generally indicated for bilateral simultaneous TKAs. After preoperative clearance from the primary physician and/or specialists as necessary, the decision for bilateral TKA was at the judgment of the operating surgeons. Input from anesthesia occurred at the time of the surgery as the procedure was performed in a sequential fashion allowing for the surgery to be restrained to a single limb if anesthesia identified concerns at the completion of the first TKA. The current retrospective, comparative series compared generally sequential groups in terms of TXA usage. Between August 2013 and July 2015, we used two TXA doses. Patients received 1 g of intravenous TXA as a bolus immediately after the last tourniquet release and were given a 1-g intravenous bolus 6 hours after the initial dose. A total of 167 patients were treated with this approach, of whom 96% (161) are fully analyzed here. Between August 2015 and October 2016, our approach changed to a single TXA dose. The dosing regimen change occurred as a group decision for change of practice and occurred mid-year to coincide with the fellowship year cycle. Patients received a 1-g bolus of intravenous TXA immediately after the final tourniquet release. A total of 105 patients were treated with this approach, of whom 89% (93) are fully analyzed here. An additional 37 patients were excluded because they did not receive any TXA because of a medical contraindication such as history of venous thromboembolism, history of thrombotic stroke, cardiac stent in the past 2 years, atrial fibrillation, or long-term anticoagulation therapy. We compared patients who received one versus two doses in terms of blood loss, transfusion usage, and 30-day major complications. The mean age was 65 years for patients receiving one dose and 67 years for patients receiving two doses (p = 0.17). The one-dose group comprised 67% (62 of 93) women and the two-dose group comprised 61% (98 of 161) women (p = 0.36). Blood loss was defined as change in the hemoglobin level (the last recorded value before discharge subtracted from the preoperative value). During the study period, the decision to transfuse was based on a hemoglobin level less than 8.0 g/dL or at higher levels for symptomatic patients, patients with cardiac disease, or at the discretion of the attending surgeon. We defined complications as major medical events that included cerebrovascular accidents, myocardial infarction, deep vein thrombosis, and pulmonary embolism. With the numbers available, there was no difference in blood loss between patients treated with one and those treated with two doses of TXA (mean hemoglobin decrease -3.5 ± 1.2 g/dL versus -3.5 ± 1.0 g/dL, respectively; mean difference 0.03 g/dL [95% CI -0.2 to 0.3 g/dL]; p = 0.80). No patient in either group received a transfusion. There was no difference in the proportion of patients in either group who experienced a cerebrovascular accident (0% [0 of 93] versus 1% [1 of 161]; p > 0.99), deep vein thrombosis (1% [1 of 93] versus 0% [0 of 161]; p = 0.37), or pulmonary embolism (1% [1 of 93] versus 1% [1 of 161]; p > 0.99). No patient in either the one-dose or two-dose TXA groups experienced a myocardial infarction. The findings of this study suggest that a single dose of intravenous TXA may be adequate to control excessive blood loss and reduce blood transfusion in simultaneous bilateral TKA. Despite its short half-life, TXA still appears to be effective in this demanding procedure without requiring prolonged plasma concentrations obtained from multiple doses. Additional high-quality studies are still needed to determine the most appropriate dosing regimen. Level III, therapeutic study.