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Background: Total joint arthroplasty (TJA) episodic payment models shift risk and cost of periprosthetic joint infection (PJI) to surgeons and hospitals, causing some to avoid treating high-risk patients. Furthermore, there are little data to support optimization of host factors preoperatively to decrease PJI, and recent literature supports using extended antibiotic prophylaxis following reimplantation TJA. The purpose of this study was to evaluate whether extended oral antibiotic prophylaxis minimized PJI after primary TJA in high-risk patients.Methods: A retrospective cohort study was performed of 2,181 primary total knee arthroplasties (TKAs) and primary total hip arthroplasties (THAs) carried out from 2011 through 2016 at a suburban academic hospital with modern perioperative and infection-prevention protocols. Beginning in January 2015, extended oral antibiotic prophylaxis for 7 days after discharge was implemented for patients at high risk for PJI. The percentages of patients diagnosed with PJI within 90 days were identified and compared between groups that did and did not receive extended oral antibiotic prophylaxis, with p ≤ 0.05 indicating significance.Results: The 90-day infection rates were 1.0% and 2.2% after the TKAs and THAs, respectively. High-risk patients without extended antibiotic prophylaxis were 4.9 (p = 0.009) and 4.0 (p = 0.037) times more likely to develop PJI after TKA and THA, respectively, than high-risk patients with extended antibiotic prophylaxis.Conclusions: Extended postoperative antibiotic prophylaxis led to a statistically significant and clinically meaningful reduction in the 90-day infection rate of selected patients at high risk for infection. We encourage further study and deliberation prior to adoption of a protocol involving extended oral antibiotic prophylaxis after high-risk TJA, with the benefits weighed appropriately against potential adverse consequences such as increasing the development of antimicrobial resistance.Level Of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]