Objectives: To determine whether systemic inflammation is associated with poor proprioception; to confirm that systemic inflammation is associated with muscle weakness; and to determine whether poor proprioception mediates the association between systemic inflammation and muscle weakness in knee osteoarthritis. Design: Cross-sectional study. Subjects: A total of 689 participants with knee osteoarthritis from the Amsterdam Osteoarthritis (AMS-OA) cohort. Methods: Systemic inflammation was assessed by erythrocyte sedimentation rate, knee proprioception by determining the joint motion detection threshold, and muscle strength with an isokinetic dynamometer. Linear regression models were used to estimate direct associations between systemic inflammation, proprioception and muscle strength, and the indirect association (mediation) between systemic inflammation and muscle strength via proprioception adjusted for potential confounders. Results: Higher erythrocyte sedimentation rates were associated with poor proprioception (p = 0.022). Poor proprioception (p < 0.001) and higher erythrocyte sedimentation rates (p < 0.001) were associated with muscle weakness. Poor proprioception mediated the association between systemic inflammation and muscle weakness (p = 0.035). Conclusion: Results suggest that systemic inflammation is associated with poor proprioception in knee osteoarthritis. Poor proprioception may be a pathway through which systemic inflammation is associated with muscle weakness in patients with knee osteoarthritis.