Murine hepatitis virus A59 infection of the central nervous system (CNS) results in CNS demyelination in susceptible strains of mice. In infected B-cell-deficient mice, demyelination not only occurred but was also more severe than in parental C57BL/6 animals. This increase may be due to the persistence of virus in the CNS in the absence of B cells. In mice lacking antibody receptors or complement pathway activity, virus did not persist yet demyelination was similar to parental mice. In infected RAG1(-/-) mice, moderately sized, typical demyelinating lesions were identified. Therefore, demyelination can occur in the absence of B and T cells.