Background Children and adults with the lysosomal storage diseases mucopolysaccharidosis (MPS) types I, II and VI live shortened lives permeated by chronic pain and physical disability. Current treatments do not alleviate these problems. Thus there is a critical need to understand the mechanism of chronic pain and disability in MPS in order to improve the way we treat patients. A potential target is inflammation. Hypothesis We hypothesized that excessive inflammation mediated by the tumor necrosis factor-α (TNF-α) inflammatory pathway is the fundamental cause of much of the chronic pain and physical disability in MPS. Methods 55 patients with MPS I, II, or VI were enrolled over the course of a 5-year prospective longitudinal natural history study and evaluated annually for 2–5 years. 51 healthy controls were enrolled in a separate cross-sectional study of bone and energy metabolism. TNF-α was measured by ELISA. Pain and physical disability were measured by the Children's Health Questionnaire – Parent Form 50 (CHQ-PF50). Differences in log-transformed TNF-α levels and associations with CHQ domains were evaluated using a linear mixed effects model with random intercept. Results TNF-α levels were measured in 48 MPS (age: 5–17 years; 35% female) and 51 controls (age: 8–17 years; 53% female). Among MPS, 22 (46%) were treated with hematopoietic cell transplantation (HCT) alone, 24 (50%) with enzyme replacement therapy (ERT) alone, and 2 (4%) with both HCT and ERT. TNF-α levels are higher in MPS compared to healthy controls (p < 0.001). Higher TNF-α levels are associated with increased pain and decreased physical function, social limitations due to physical health, and physical summary score (all p < 0.05). TNF-α levels were not significantly associated with the general health score. TNF-α levels did not change significantly over time in MPS. Conclusions Higher TNF-α levels are implicated in the pain and decreased physical function present in individuals with MPS despite treatment with ERT and/or HCT, suggesting that TNF-a inhibition could potentially be a useful adjunctive therapy. Further investigation into the role of TNF-α inhibition in MPS to decrease pain and improve physical function is indicated.