Multiple Sclerosis (MS), an immune-mediated disease of the central nervous system (CNS), is characterized by chronic neuroinflammation and demyelination. Interleukin-6 (IL-6), a major cytokine released by monocytes and macrophages, promotes a robust downstream inflammatory cascade, including the release of C-Reactive Protein (CRP), a common clinical marker of inflammation. Physical activity is known to be protective against inflammation and recent evidence suggests that increasing soluble form of the receptor for advanced glycation endproducts (sRAGE) may be an additional mechanism by which this occurs. PURPOSE: To characterize the relationship between fitness and inflammatory markers (CRP, IL-6) in persons with MS, and to elucidate the effects of a 12-week home-based exercise program on inflammation, estimates of insulin resistance (HOMA-IR), circulating sRAGE, and fitness in persons with MS. METHODS: Forty-eight participants with MS (45±2 yrs, 28.8±0.9 kg/m 2, 35 females) were randomly assigned to either a home-based aerobic exercise program or an attention-control stretching group. The exercise intervention consisted of cycling 3-4 d/wk at 40-60% VO2 peak 30 min/d. VO2 peak was assessed using open-circuit spirometry on a cycle ergometer. Blood was drawn at baseline and following the 12-week intervention and plasma metabolites were assessed using commercially available ELISA kits. RESULTS: Baseline VO2 peak was negatively correlated with baseline plasma levels of CRP (r=-0.43, p=<0.01) and IL-6 (r=-0.51 p<0.01). VO2 peak increased 8% in individuals with MS (p<.001), with no change in the attention-control group. No between or within group differences were observed for sRAGE, IL-6, CRP or HOMA-IR. CONCLUSION: Despite no effect of the exercise intervention, the relationship between VO2 peak and CRP, IL-6 at baseline suggest that higher fitness levels are advantageous to individuals with MS and may be related to the well-known anti-inflammatory effects of exercise. This relationship is promising for the use of exercise on modulating cellular inflammation in individuals with MS, however longer duration, higher intensity or supervised exercise may be necessary in order to elicit changes in circulating IL-6, CRP, sRAGE and HOMA-IR. Supported by the National Multiple Sclerosis Society RG 4702A1/2.