Relapse-remitting multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that affects more than 2.5 million individuals worldwide. While the etiology of MS is unclear, disease manifestation involves proliferation and activation of lymphocytes and astrocytes, leading to demyelination and neuronal damage. Current therapies are not completely effective, and few target the underlying pathophysiology of MS. The purpose of this study was to examine the therapeutic efficacy of a novel biological pathway, the opioid growth factor (OGF)-OGF receptor (OGFr) axis. OGF inhibits DNA synthesis and has been shown to repress proliferation of T lymphocytes, microglia, and astrocytes in other autoimmune disorders. An animal model for relapse-remitting experimental autoimmune encephalomyelitis (RR-EAE) was established by immunization of SJL/J mice with proteolipid protein. Treatment with OGF or saline was initiated simultaneously with immunization, and within 9 days, behavioral signs of RR-EAE were observed. OGF-treated RR-EAE animals had less severe clinical disease than mice receiving saline and exhibited 66% reductions in median cumulative disease scores, as well as prolonged periods of remission and diminished number and length of disease relapses. Neuropathological examination of lumbar spinal cord revealed reductions in the number of T lymphocytes, microglia/macrophages, and activated astrocytes, with cell proliferation being the mechanism targeted by OGF. Areas of demyelination and neuronal damage were markedly reduced during the 55-day observation period. These data are the first to demonstrate that OGF prevented relapses in RR-EAE and diminished underlying neuropathology, corroborating the potential of the OGF-OGF receptor pathway for treatment of MS.