Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Like MS, the animal model experimental autoimmune encephalomyelitis (EAE) is characterized by CNS inflammation and demyelination and can follow a relapsing–remitting (RR) or chronic (CH) disease course. The molecular and pathological differences that underlie these different forms of EAE are not fully understood. We have compared the differences in RR‐ and CH‐EAE generated in the same mouse strain (C57BL/6) using the same antigen. At the peak of disease when mice in both groups have similar clinical scores, CH‐EAE is associated with increased lesion burden, myelin loss, axonal damage, and chemokine/cytokine expression when compared with RR‐EAE. We further showed that inflammation and myelin loss continue to worsen in later stages of CH‐EAE, whereas these features are largely resolved at the equivalent stage in RR‐EAE. Additionally, axonal loss at these later stages is more severe in CH‐EAE than in RR‐EAE. We also demonstrated that CH‐EAE is associated with a greater predominance of CD8⁺ T cells in the CNS that exhibit MOG_35–55 antigen specificity. These studies therefore showed that, as early as the peak stage of disease, RR‐ and CH‐EAE differ remarkably in their immune cell profile, chemokine/cytokine responses, and histopathological features. These data also indicated that this model of CH‐EAE exhibits pathological features of a chronic‐progressive disease profile and suggested that the sustained chronic phenotype is due to a combination of axonal loss, myelin loss, and continuing inflammation. © 2009 Wiley‐Liss, Inc.