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Background: Increasing antibiotic resistance has been reported as an issue in the systemic treatment of periprosthetic joint infection (PJI). Linezolid offers the advantages of high oral bioavailability and little resistance; however, efficacy in the treatment of PJI varies considerably, and studies reporting consistent surgical treatment are scarce. Methods: This is a retrospective, single-center analysis of two-stage revisions performed between 2008 and 2017. We identified 111 patients who met the inclusion criteria. Oral linezolid was given for 28 days following 14 days of intravenous tailored antibiotics in resistant gram-positive PJI. A total of 64% of the patients had methicillin-resistant coagulase-negative staphylococci. The median follow-up was 43 (interquartile range (IQR) 30–57) months. Results: 22% (24/111) of the patients underwent surgery for subsequent infection. The 5-year infection-free survival probability was 77% (95% confidence interval (CI) 69–85). A total of 5% of the patients (6/111) had the same organism at the time of reinfection. The patients with infections caused by other organisms than Coagulase-negative staphylococci tended to have a worse reinfection-free survivorship at five years (70% vs. 81%, p = 0.09). Furthermore, the patients with obesity tended to have reduced reinfection-free survivorship at five years (69% vs. 84%, p = 0.08). Overall, 5% (6/111) of the patients had blood count abnormalities with no treatment discontinuations. Conclusion: Two-stage revision arthroplasty with systemic oral linezolid treatment for resistant gram-positive PJI results in an infection control of 77% at the mid-term. [ABSTRACT FROM AUTHOR]