The antiviral role of CD4+ T cells in virus-induced pathologies of the central nervous system (CNS) has not been explored extensively. Control of neurotropic mouse hepatitis virus (JHMV) requires the collaboration of CD4+ and CD8+ T cells, with CD8+ T cells providing direct perforin and gamma interferon (IFN-ฮณ)-mediated antiviral activity. To distinguish bystander from direct antiviral contributions of CD4+ T cells in virus clearance and pathology, memory CD4+ T cells purified from wild type (wt), perforin-deficient (PKO), and IFN-ฮณ-deficient (GKO) immune donors were transferred to immunodeficient SCID mice prior to CNS challenge. All three donor CD4+ T-cell populations controlled CNS virus replication at 8 days postinfection, indicating IFN-ฮณ- and perforin-independent antiviral function. Recipients of GKO CD4+ T cells succumbed more rapidly to fatal disease than untreated control infected mice. In contrast, wt and PKO donor CD4+ T cells cleared infectious virus to undetectable levels and protected from fatal disease. Recipients of all CD4+ T-cell populations exhibited demyelination. However, it was more severe in wt CD4+ T-cell recipients. These data support a role of CD4+ T cells in virus clearance and demyelination. Despite substantial IFN-ฮณ-independent antiviral activity, IFN-ฮณ was crucial in providing protection from death. IFN-ฮณ reduced neutrophil accumulation and directed macrophages to white matter but did not ameliorate myelin loss. Copyright ยฉ 2008, American Society for Microbiology.