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Purpose: We performed a systematic review and meta-analysis of the literature to evaluate the efficacy of the routine use of tranexamic acid (TXA) during percutaneous nephrolithotomy (PCNL). Methods: This systematic review was conducted following the updated reporting guidelines from PRISMA 2020. Results: In total, 275 titles and abstracts were reviewed, of which 20 were screened to be eligible for full text review. Of these 20 articles, 11 were selected for inclusion after full article evaluations. Seven of these 11 studies were seen as having a low risk of bias with a Jadad score of ≥3. These studies were included for data extraction. Once data were extracted, 964 patients were included. The primary outcome, blood transfusion rate, showed significant reduction with a ratio for transfusion rate of 0.34 [95% confidence interval (CI) (0.19 to 0.61), z = 3.61, p = 0.0003]. Mean hemoglobin (Hgb) drop and operative time were both shown to be reduced with the use of TXA. The mean difference for Hgb drop was −0.86 [95% CI (−1.26 to −0.46), z = 4.23, p < 0.0001]. Reduction in operative time showed a mean difference of −8.45 minutes [95% CI (−15.04 to −1.86), z = 2.51, p = 0.01]. Stone clearance was not shown to differ significantly between experimental and control groups, with a risk ratio of 1.28 [95% CI (0.89 to 1.84), z = 1.31, p = 0.19]. Conclusions: This meta-analysis revealed that the routine use of TXA at time of PCNL reduces the rates of blood transfusion, mean Hgb drop, and operative time. With the low cost of TXA and strong safety profile, stronger consideration should be given to the routine use of TXA during PCNL by endoscopic surgeons. [ABSTRACT FROM AUTHOR]