Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) where immune cells attack the protective myelin sheath surrounding axons, causing permanent neuronal damage. Targeting immune cell trafficking into the CNS is an effective treatment for MS. However, complete abolishment of immune surveillance by some MS drugs, like natalizumab, can have deadly side effects such as progressive multifocal leukoencephalopathy. Normally, the tightly controlled blood brain barrier (BBB) protects the CNS from inflammation by restricting, but not completely inhibiting, the entrance of immune cells. In MS, enzymes released at the BBB contribute to its breakdown. One such enzyme, heparanase, has been suggested as a therapeutic target for drug development in neuroinflammatory disorders as this enzyme can be selectively inhibited by heparan sulfate (HS) mimetics. Historically, HS-mimetics have struggled to get past pre-clinical studies due to the complexity in their synthesis and anti-coagulant effects. The novel HS mimetic used in the current studies is relatively inexpensive and quick to synthesise, and has low anti-coagulant properties. Our lab has found that therapeutic administration of this mimetic significantly reduces disease in experimental autoimmune encephalomyelitis (EAE), a murine model of MS. By maintaining integrity of the BBB, entrance of immune cells into the CNS is significantly reduced. Interestingly, this inhibition of inflammatory trafficking does not correspond with reduced homeostatic trafficking into the CNS as quantified by flow cytometry. Moreover, in vivo migration studies using CCL2 and CCL5 as chemoattractants suggest that treatment with this HS-mimetic maintains chemokine gradients, which may enhance homeostatic trafficking in healthy animals. These findings suggest that this HS-mimetic selectively reduces neuroinflammatory trafficking, whilst maintaining the immune surveillance that is essential for the homeostasis of the CNS.