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Background: A number of clinical trials have been conducted, assessing the role of long-term (>1 year) suppressive antibiotic treatment (SAT) combined with Debridement, Antibiotics, and Implant Retention (DAIR) for the management of peri-prosthetic joint infection (PJI). However, no systematic review of the literature has been published to date to evaluate complications associated with long-term antibiotic treatment and overall survivorship free from re-operation and revision for infection after DAIR for total hip and total knee PJI. Methods: The US National Library of Medicine (PubMed/MEDLINE), EMBASE, and the Cochrane Database of Systematic Reviews were queried for publications from January 1980 to December 2018 utilizing keywords pertinent to total knee arthroplasty, total hip arthroplasty, PJI, and antibiotic suppression. Results: Overall, 7 articles of low quality (level III or IV) were included in this analysis. The studies included in this systematic review included 437 cases of PJI treated surgically with DAIR and then with SAT. The overall mean infection-free rate of SAT following DAIR was 75% (318/424 patients), while the all-cause re-operation rate was 6.7%. Overall, the mean rate of adverse effects associated with long-term antibiotic use was 15.4% and the mean rate of adverse effects leading to discontinuation of SAT was 4.3%. There was no study to show significant differences between acute (either post-operative or hematogenous, with onset of symptoms ≤4 weeks) and chronic (onset of symptoms >4 weeks) infections and failure rates of DAIR with SAT. The literature is inconclusive on the influence of anatomic location (hip vs knee) as well as microorganism on the success rate of DAIR with SAT. Conclusion: The results of this systematic review demonstrate that there is still only low-quality evidence regarding the therapeutic effect of DAIR combined with SAT, which is not enough to draw definitive conclusions. Furthermore, high-quality prospective studies are needed to better understand SAT's efficacy and safety in a controlled fashion. Although discontinuation of antibiotic treatment due to side effects was found to be low, the high rates of adverse effects noted after DAIR with SAT demonstrate the underlying frailty and complexity of many patients with PJI, and the imperfect therapies available. Although Staphylococcus aureus appears to be a risk factor for increased risk of SAT failure, there are not enough data to establish which patients would benefit most from DAIR with post-operative SAT.