An endogenous neuropeptide, opioid growth factor (OGF), chemically termed [Met(5)]-enkephalin, arrested the progression of established disease in a mouse model of multiple sclerosis (MS) called experimental autoimmune encephalomyelitis (EAE). This study treated mice who demonstrated 2 consecutive days of behavioral decline following injections of myelin oligodendrocyte glycoprotein (MOG) with daily injections of OGF (10mg/kg) or saline (0.1ml) for 40 days. Within 6 days of OGF treatment, mice initially demonstrating clinical signs of EAE had significant reductions (45% reduction) in their behavioral scores relative to EAE mice receiving saline. Behavior was attenuated for the entire 40-day period with mice receiving OGF showing only limp tails and wobbly gait in comparison to saline-treated EAE mice who displayed paralysis of one or more limbs. Neuropathological studies revealed that OGF treatment initiated after the appearance of disease reduced the number of activated astrocytes and damaged neurons, decreased demyelination, and inhibited T cell proliferation. These results demonstrate that OGF can halt the progression of established EAE, return aberrant pain sensitivity to normal levels, inhibit proliferation of T cells and astrocytes, and prevent further spinal cord pathology. The data extend our observations that OGF given at the time of disease induction prevented disease onset, reduced the severity of clinical signs of disease, and reversed neurological deficits in a non-toxic manner. Our data substantiate the role of the OGF-OGFr axis in EAE and support the use of OGF as a biotherapy for MS.