We used genetic deletion of beta2-microglobulin to study the influence of CD8(+) T cells on spinal cord demyelination, remyelination, axonal loss and brainstem N-acetyl aspartate levels during the acute and chronic phases of Theiler's murine encephalomyelitis virus (TMEV) infection. We used beta2m(-/-) and beta2m(+/+) B10.Q mice (of H-2(q) background) normally susceptible to TMEV-induced demyelination. Over the disease course, beta2m(+/+) mice had increasing levels of demyelination and minimal late-onset remyelination. In contrast, beta2m(-/-) mice had steady levels of demyelination from 45-390 dpi and remyelination was extensive and more complete. Early in the disease, brainstem NAA levels drop in both strains, but accordingly with remyelination and axonal preservation, NAA recover in beta2m(-/-) mice despite equivalent brainstem pathology. At 270 dpi, beta2m(+/+) mice had significantly fewer spinal cord axons than beta2m(-/-) mice (up to 28% less). In addition, beta2m(+/+) mice lost axons of all calibers, whereas beta2m(-/-) mice had a modest loss of only medium- and large-caliber axons. This study further supports the hypothesis that CD8(+) T cells are involved in demyelination, and axonal loss following Theiler's virus-induced demyelination.