Infection of rodents with murine coronavirus JHM results in a subacute or chronic demyelinating disease which serves as a model for the human disease multiple sclerosis. Previous studies with JHMV have established a role for the immune system in both viral clearance and demyelination. To further clarify the role of the immune system in JHMV pathogenesis, several strains of congenitally immunodeficient mice were studied. Infection of immunocompetent C57BL/6 mice with JHMV resulted in severe paralysis and demyelination and complete clearance of infectious virus from the brain (C^-D^- phenotype). In contrast, infected SCID mice showed little or no paralysis or demyelination and were unable to clear infectious virus (C⁻D⁺ phenotype). Athymic nude mice and a proportion of mice lacking MHC Class I or II expression exhibited robust demyelination but did not completely clear infectious virus from the brain (C^-D⁺ phenotype). These results are consistent with an immune-mediated mechanism for JHMV-induced demyelination, but indicate that the immune mechanisms which participate in demyelination and viral clearance are distinct. It may thus be possible to experimentally alter immunopathological responses without impairing antimicrobial immunity.