Background: Revision total joint arthroplasty (TJA) has a higher rate of periprosthetic joint infection (PJI) compared with primary TJA, possibly as the result of increased allogeneic blood transfusion. Tranexamic acid (TXA) is gaining popularity in revision TJA to minimize blood loss and the need for transfusion; however, its effect on PJI reduction has yet to be investigated. The hypothesis of this study was that the administration of TXA during revision arthroplasty is protective against subsequent PJI. Methods: A prospectively maintained institutional database was used to identify patients who underwent revision TJA for aseptic failure from 2009 to 2018 and had a minimum follow-up of 90 days. Patients who developed PJI following revision arthroplasty were identified. All patients with PJI met Musculoskeletal Infection Society (MSIS) criteria. A multivariate analysis was performed to identify variables independently associated with PJI after aseptic revision TJA. Results: Overall, 1,731 patients who underwent aseptic revision were identified; of these patients, 83 (4.8%) developed PJI. Patients who received TXA had significantly lower rates (p = 0.029) of PJI postoperatively at 3.30% compared with those who did not receive TXA at 5.73%. After controlling for relevant confounding variables, TXA remained a significant independent factor that protected against PJI (odds ratio [OR], 0.47 [95% confidence interval (CI), 0.23 to 0.90]; p = 0.030). Female sex was also identified as a significant independent factor that protected against PJI (OR, 0.52 [95% CI, 0.30 to 0.88]; p = 0.016). However, preoperative anemia was independently associated with an increased risk of subsequent PJI (OR, 2.37 [95% CI, 1.34 to 4.16]; p = 0.003). Conclusions: Based on this study conducted at a single institution, the use of TXA during aseptic revision arthroplasty was independently associated with a reduced risk of subsequent acute PJI after adjusting for multiple patient characteristics and surgical factors. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.