ABSTRACT Replication of the neurotropic mouse hepatitis virus strain JHM (JHMV) is controlled primarily by CD8 + T-cell effectors utilizing gamma interferon (IFN-γ) and perforin-mediated cytotoxicity. CD4 + T cells provide an auxiliary function(s) for CD8 + T-cell survival; however, their direct contribution to control of virus replication and pathology is unclear. To examine a direct role of CD4 + T cells in viral clearance and pathology, pathogenesis was compared in mice deficient in both perforin and IFN-γ that were selectively reconstituted for these functions via transfer of virus-specific memory CD4 + T cells. CD4 + T cells from immunized wild-type, perforin-deficient, and IFN-γ-deficient donors all initially reduced virus replication. However, prolonged viral control by IFN-γ-competent donors suggested that IFN-γ is important for sustained virus control. Local release of IFN-γ was evident by up-regulation of class II molecules on microglia in recipients of IFN-γ producing CD4 + T cells. CD4 + T-cell-mediated antiviral activity correlated with diminished clinical symptoms, pathology, and demyelination. Both wild-type donor CD90.1 and recipient CD90.2 CD4 + T cells trafficked into the central nervous system (CNS) parenchyma and localized to infected white matter, correlating with decreased numbers of virus-infected oligodendrocytes in the CNS. These data support a direct, if limited, antiviral role for CD4 + T cells early during acute JHMV encephalomyelitis. Although the antiviral effector mechanism is initially independent of IFN-γ secretion, sustained control of CNS virus replication by CD4 + T cells requires IFN-γ.