Interleukin 10 (IL-10) is an important anti-inflammatory cytokine. To examine its role in virus-induced encephalomyelitis, IL-10-deficient (IL-10 -/-) mice were infected with a neurotropic strain of mouse hepatitis virus (JHMV). JHMV-infected IL-10 -/- mice, compared to IL-4 -/- and syngeneic C57BL/6 mice, exhibited increased morbidity and mortality. Virus was cleared from the CNS of all groups of mice with equal kinetics by day 9 postinfection and the lack of either IL-4 or IL-10 did not alter the distribution of viral antigen, suggesting a lack of correlation between viral replication and the increased clinical disease in IL-10 -/- mice. In moribund IL-10 -/- mice, a moderate increase in mononuclear cell infiltration was correlated with increased expression of tumor necrosis factor-alpha, interferon-gamma, and inducible nitric oxide synthase mRNAs. In the small percentage of IL-10 -/- mice that survived, no differences in either demyelination or inflammation were observed. Together, these results suggest that IL-10 is not required for viral clearance, and although it appears to be one of the mechanisms responsible for inhibiting the extent of inflammation in the CNS during acute JHMV infection, it has little role in the eventual resolution of CNS inflammatory responses.