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Background: The relationship between systemic inflammatory processes to total knee arthroplasty (TKA) outcomes remains unclear. This study investigates the relationship between serum high-sensitivity C-reactive protein (hs-CRP) and functional outcomes post-TKA., Methods: A total of 31 patients with osteoarthritis (OA) who underwent TKA were enrolled in the study; 15 with hs-CRP ≤1.0 mg/l (low hs-CRP group) and 16 subjects with hs-CRP ≥4.0 mg/l (high hs-CRP group). During surgery, synovium and bone sections were sequestered, formalin-fixed, and paraffin embedded for slide preparation. Tissue sections were stained with hematoxylin and eosin and analyzed using a light microscope. A total of 12 cytokines were measured in synovial fluid samples from the knee joint at time of surgery and analyzed using the Luminex Multi-Analyte Profiling System. Relationships between cytokines and hs-CRP were assessed using Spearman correlation coefficients. Student's t-tests were used to compare Short Form health outcomes survey (SF-12) health outcomes between high and low hs-CRP, and presurgical and postsurgical visits., Results: Mean ± standard deviation (SD) baseline and 1-year hs-CRP values for the low hs-CRP group were 0.55 ± 0.23 mg/l and 1.22 ± 1.32 mg/l, respectively (n = 15; p = 0.051) and for the high hs-CRP group were 7.86 ± 5.98 mg/l and 14.11 ± 38.9 mg/l, respectively (n = 13; p = 0.54). Lymphocytes were present in 10 synovium and one bone sample (all but one from high hs-CRP group). Interleukin (IL)-5 and IL-10 were significantly correlated with hs-CRP (p = 0.0137 and p = 0.0029, respectively). The low hs-CRP group exhibited significant improvement in the physical component of SF-12 at 6 and 12 months compared with baseline, whereas the high hs-CRP group exhibited significant improvement only at 6 months. Body mass index (BMI) had a significant positive correlation with presurgical hs-CRP., Conclusions: The results of this study provide support for inflammatory mechanisms contributing to the OA progression, with hs-CRP being a possible predictive variable, combined with BMI and other comorbidities, of post-TKA function.