Multiple sclerosis is an immune-mediated demyelinating disease, with axonal loss underlying long-term progressive disability. In this study, we have analyzed axonal and myelin pathology in a chronic relapsing-remitting experimental autoimmune encephalomyelitis model in Biozzi ABH mice induced by immunization with a syngeneic spinal cord homogenate. The animals were followed for3 months; inflammation, T-cell infiltration, demyelination, and axonal loss were examined at various time points throughout the disease course. We found that macrophage infiltration and microglia activation preceded detectable T-cell infiltration. Axonal loss was first evident at the acute phase of disease before demyelination was detected. Demyelination and axonal loss occurred after each relapse and correlated with increasing residual motor deficits in remission. The resulting lesions displayed evidence of demyelination, remyelination, axonal degeneration, and axon loss. After a series of 3 relapses, animals entered a chronic progressive phase with permanent paralysis and a relative absence of inflammation. Axonal loss continued in this phase, although demyelinated axons persisted. These findings indicate that experimental autoimmune encephalomyelitis in Biozzi ABH mice has important similarities to multiple sclerosis with a relapsing-remitting disease course followed by a secondary progressive phase; it is thus a suitable model in which to explore remyelination and neuroprotective therapies for multiple sclerosis.