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Background: Patients with advanced knee arthritis who develop a septic joint are not adequately treated with irrigation and debridement and intravenous antibiotics because of antecedent cartilage damage. The gold standard treatment has been a 2-stage approach. The periprosthetic joint infection literature has demonstrated the superiority of articulating spacers, and metal-on-poly (MOP) spacers are being used with increasing frequency. The purpose of this study was to compare the postoperative outcomes of patients with infected, arthritic knees treated by a 2-stage approach to those of patients who received single-stage treatment with a MOP spacer. Methods: Sixteen patients with native knee septic arthritis treated with an antibiotic spacer between 1998 and 2019 were reviewed. Demographic data, clinical data, knee motion, Knee Society score, Timed-Up-and-Go, and pain scores were collected. Survivorship of final implants was compared. Results: Six of 16 knees (38%) received single-stage treatment, and 10 received 2-stage treatment (62%). Five of 6 MOP spacers (83%) were retained at a mean follow-up of 3 ± 1.2 years. Nine of 10 (90%) receiving static spacers had subsequent reconstruction, with 9 (100%) surviving at mean follow-up of 7 ± 3.2 years. The patients who received MOP spacers trended toward greater terminal flexion, higher Knee Society score, and faster Timed-Up-and-Go at final follow-up. Conclusion: Infection in a native, arthritic knee may be effectively treated using single-stage MOP spacer. Postoperative outcomes of single-stage MOP spacers compare favorably to staged static spacers and with those undergoing revision surgery for other indications. Longer follow-up is needed to evaluate durability of MOP spacers.