Background: Treatment with a static or an articulating antibiotic-containing spacer is a common strategy for treating periprosthetic joint infection (PJI), yet many patients have persistent infections after spacer treatment. Although previous studies have compared the efficacy of a static and articulating spacer for treating PJI, few studies have assessed infection control from the time of spacer implantation, or they defined treatment failure as including reinfection, reoperation, or chronic suppressive therapy. Additionally, few studies have examined whether there is an interaction between spacer and pathogen type with respect to treatment success., Questions/purposes: (1) Is there a difference in failure-free survival (defined as no reoperation, reinfection, or suppressive antibiotic therapy) between static and articulating spacers after spacer implantation for PJI? (2) Did the relationship between spacer type and failure-free survival differ by pathogen type (staphylococcal versus nonstaphylococcal and difficult-to-treat [including methicillin-resistant Staphylococcus aureus, methicillin-susceptible S. aureus, Corynebacterium, Mycobacterium, Enterococcus spp, and other gram-negative bacterium] versus not-difficult-to-treat organisms)?, Methods: Between January 2014 and January 2022, a convenience sample of 277 patients was identified as having knee PJIs treated with an articulating (75% [208 of 277]) or static (25% [69 of 277]) antibiotic spacer and potentially eligible for this study. During that time, providers at our institution generally used spacers for later-presenting or chronic infections. Spacer choice was determined by surgeon preference, with static spacers used more often in instances of higher bone loss and poor soft tissue coverage. Thirty-one patients (8 static and 23 articulating spacers) were considered lost to follow-up or had incomplete datasets and were excluded from the analysis, resulting in a final analysis cohort of 246 patients: 25% (61 of 246) received a static spacer and 75% (185 of 246) received an articulating spacer. The mean ± standard deviation age of patients was 66 ± 9.9 years, BMI was 33.3 ± 6.9 kg/m2, and Elixhauser score was 18.1 ± 16.9. Demographic and clinical characteristics were similar between the two groups. Pathogen type was collected and categorized as staphylococcal versus nonstaphylococcal, and difficult-to-treat (including methicillin-resistant Staphylococcus aureus, methicillin-susceptible S. aureus, Corynebacterium, Mycobacterium, Enterococcus spp, and other gram-negative bacterium) versus not-difficult-to-treat, as defined by an infectious disease physician. Other variables we collected included sex, age, American Society of Anesthesiologists classification, BMI, and Elixhauser score. The primary outcome of interest was failure-free survival, which was a composite time-to-event outcome, with failure defined as reoperation, reinfection, death owing to infection, or chronic antibiotic use at a minimum of 1 year after the completion of the patient's Stage 1 postoperative antibiotic course, whichever came first. Reinfection was determined by the treating physicians in accordance with the Musculoskeletal Infection Society guidelines and included an evaluation of infectious laboratory values, cultures, and clinical signs of infection. We compared static and articulating spacers using a Cox proportional hazards model, with spacer type as the primary predictor variable. We compared staphylococcal versus nonstaphylococcal and difficult-to-treat versus not-difficult-to-treat infections by running additional models with interaction terms between spacer type and pathogen type., Results: No difference was observed in the cause-specific hazard ratio for static versus articulating (reference) spacers (HR 1.45 [95% confidence interval 0.94 to 2.22]; p = 0.09), after adjusting for covariates. Additionally, no difference in the association between spacer type and failure-free survival was found between pathogen types or treatment difficulty after evaluating interactions (staphylococcal HR 0.37 [95% CI 0.15 to 0.91], nonstaphylococcal HR 0.79 [95% CI 0.49 to 1.28]; p value for interaction = 0.14; difficult-to-treat HR 0.37 [95% CI 0.14 to 0.99], not-difficult-to-treat HR 0.75 [95% CI 0.47 to 1.20]; p value for interaction = 0.20)., Conclusion: The lack of a difference in failure-free survival and insufficient evidence of a difference in the association between spacer type and treatment failure by pathogen type suggests that infectious organism may not be an important consideration in the decision about spacer treatment type. Further studies should aim to elucidate which patient factors are the most influential in surgeon decision-making when choosing a spacer type in patients with PJI of the knee.Level of Evidence Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2024 by the Association of Bone and Joint Surgeons.)