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Background: Periprosthetic joint infection (PJI) is a devastating complication of total joint arthroplasty (TJA). Rifampin is an antibiotic with the ability to penetrate bacterial biofilms, and thus has been considered as a potentially important adjunct in the prevention and treatment of PJI. The aim of this systematic review is to evaluate and summarize the use of rifampin in TJA, particularly in the context of PJI. Methods: A literature search of all relevant electronic databases was performed. All comparative studies assessing the use of rifampin in the context of TJA were included. Descriptive data are reported, and a meta-analysis was performed using all studies which compared the addition of rifampin to standard care in treating PJI. Results: A total of 33 studies met inclusion criteria. A meta-analysis of 22 studies comparing the addition of rifampin to standard care for treating PJI found a significant reduction in failure rates (26.0% vs 35.9%; odds ratio 0.61, 95% confidence interval 0.43-0.86). The protective effect of rifampin was maintained in studies which included exchange arthroplasty as a treatment strategy, but not in studies only using an implant retention strategy. Among studies reporting adverse events of rifampin, there was a 20.5% adverse event rate. Conclusion: Overall, rifampin appears to confer a protective effect against treatment failure following PJI. This treatment effect is particularly pronounced in the context of exchange arthroplasty. Further highlevel evidence is needed to clarify the exact indications and doses of rifampin which can most effectively act as an adjunct in the treatment of PJI.