Despite treatment with enzyme replacement therapy (ERT), the majority of individuals with mucopolysaccharidosis (MPS) type I, II or VI report significant decreased physical function and pain. In animal models of MPS, tumor necrosis factor - alpha (TNF-a) levels are increased and treatment with TNF-a inhibitors improve physical function. Therefore, our objective was to determine if TNF-a levels were increased in individuals with MPS and associated with physical function and pain. To achieve this objective, a cross-sectional study of 18 children with MPS I, II, or VI and 51 healthy children was performed. TNF-a was measured in plasma by enzyme-linked immunosorbent assay [ELISA]. Physical function and bodily pain were measured using the Children’s Health Questionnaire - Parent Form 50 (CHQ-PF50; lower score = decreased function and increased pain). Cross-sectional correlations and associations of TNF-a with CHQ outcomes were determined by Pearson correlation and linear regression adjusted for Tanner stage. TNF-a was significantly higher in children with MPS compared to healthy children (log[TNF-a] in MPS 0.8 ± 1.1 pg/ml vs. healthy -0.2 ± 0.3 pg/ml [p < .0001]). A doubling of TNF-a was associated with a change in pain score by -7.7 (95%CI -16.1 to 0.6; p = 0.069). Although the association of TNF-a with physical function was not significant when combining our entire cohort of children with MPS, within group correlation analyses showed a trend for decreased physical function with increased TNF-a levels for individuals with MPS I (R = -0.59, p = .22) and with MPS II (R = -0.38, p = .28). In conclusion, TNF-a levels are higher in children with MPS and trended toward an inverse association with CHQ-PF50 bodily pain scores after adjustment for Tanner stage. Medications that decrease TNF-a may improve physical function and decrease pain in children with MPS treated with ERT. Acknowledgements: This project was supported by Grant Number K23AR057789 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), U54NS065768 from the National Institute of Neurological Disorders and Stroke (NINDS), 1UL1RR033183-01 from the National Center for Research Resources (NCRR) and by Grant Number 8UL1TR000114-02 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) to the University of Minnesota Clinical and Translational Science Institute (CTSI).