INTRODUCTION: Tranexamic acid (TXA) is commonly used in surgical settings to reduce blood loss. Due to its antifibrinolytic properties, TXA theoretically increases the risk of thrombosis. In this study, the use of TXA was assessed in patients undergoing head and neck free flap reconstruction. METHODS: A cohort of patients from February 2021 to September 2023 received TXA. Patients received 3 g of intravenous TXA intraoperatively, in addition to topical TXA to the donor, recipient, and neck dissection sites. Patients were compared to a retrospective cohort from August 2019 to January 2021. All patients, including those in the retrospective control cohort, met the criteria for TXA. RESULTS: A total of 397 patients underwent free flap reconstruction (53.6% thigh, 25.6% fibula), of which 185 received TXA and 212 did not. Patients receiving the TXA protocol had a lower perioperative transfusion rate (12.9% vs. 20.7%, p = 0.042) and intraoperative estimated blood loss (196.4 ± 102.9 cc vs. 263.7 ± 247.8 cc, p <
0.001). There was no difference in postoperative flap vascular compromise in the TXA (7.6%) versus control (10.4%) groups (p = 0.33). Postoperative complications, including hematoma and thromboembolic events, were not statistically different between the groups. On multivariate analysis, the use of TXA remained predictive of reduced perioperative transfusion when controlling for BMI >
25, osseous flap, and hypertension. CONCLUSION: Patients who received TXA demonstrated decreased perioperative transfusion after head and neck free flap reconstruction with no increase in flap vascular compromise or major thromboembolic events. Implementation of our protocol to larger cohorts and randomized controlled trials could help identify an optimal dosing regimen and demonstrate long-term efficacy.