Objectives: This study aims to analyze the effect of intravenous administration of tranexamic acid (TA) on reducing the risk of revision for acute and delayed periprosthetic joint infection (PJI) after primary total knee replacement (TKR).Patients and methods: This prospective observational cohort study included 1,529 TKRs (396 males, 1,133 females; mean age 67.8 years; range, 44 to 85.1 years) performed between January 2003 and October 2017. We analyzed the revision rate for acute and delayed PJI in a group of 787 TKRs with preoperatively intravenously administered TA (TA group) in comparison with a group of 742 TKRs without administration of TA (non-TA group). Multiple logistic regression analysis was used to evaluate significant predictors of TKR revision for acute and delayed PJI. Results: Revision surgery due to PJI was recorded in one patient in the TA group and eight patients in the non-TA group. Cumulative revision rate of TKR was significantly lower in the TA group (0.13% vs. 1.08%, hazard ratio 0.113; 95% confidence interval [CI] 0.0147-0.937; p=0.043). Multivariate logistic regression analysis confirmed two predictors of revision: being aged over 75 years at the time of primary surgery (odds ratio [OR] 8.464; 95% CI: 2.016-35.54; p=0.004) and male gender (OR: 7.9; 95% CI: 1.879-33.26; p=0.005). The use of TA was shown as the significant protective factor (OR: 0.109; 95% CI: 0.0128-0.929; p=0.043). Conclusion: We have found a lower cumulative revision rate of TKR for acute and delayed PJI when TA was used. We think that the preoperative intravenous use of TA may be an effective, safe and inexpensive method for the prevention of PJI.