Proteoglycans are components of the extracellular matrix that have been identified as barriers to endogenous remyelination. Surfen (bis 2-methyl, 4-amino, 6-quinolyl amide) is a small molecule proteoglycan antagonist. We have previously reported that surfen reduces T cell proliferation in vivo and in vitro while also decreasing the production of chemotactic and pro-inflammatory factors produced by macrophages. Here we extend these studies to clinically relevant mouse models of chronic neuroinflammation (experimental autoimmune encephalomyelitis; EAE) and focal demyelination (lysolecithin). In the EAE model, surfen treated mice displayed a reduced disease severity that was associated with decreased percentages of CD4+CD45+ T cells and CD11b/F480 myeloid populations in the spinal cord. The chemokines RANTES, CCL2, and CCL3 were reduced in the spinal cords of surfen treated mice, resembling previous in vitro macrophage results and implicating a chemotactic mechanism that reduces cell infiltration. By contrast, when surfen was administered into a developing brain lesion using the lysolecithin model of demyelination it produced significantly larger lesions. The opposing effects of surfen observed in EAE and the lysolecithin model suggests that distinct proteoglycan families influence inflammation and remyelination differently depending on the stage of repair.