Oestrogen directly influences autoimmune diseases and the immune response to microbes. We studied the effect of oestrogen on CD4+ T cells specific for lymphocytic choriomeningitis virus (LCMV) using mice genetically engineered to be deficient in beta 2-microglobulin (beta 2m-/-). These mice are deficient in beta 2-microglobulin, class I major histocompatibility complex (MHC) molecules and CD8+ T lymphocytes. Fatal leptomeningitis after intracranial infection with LCMV is mediated by CD8+ cytotoxic T lymphocytes (CTL) in wild-type C57BL/6 mice, and by CD4+ T cells in beta 2m-/- mice. Male and female wild-type C57BL/6 mice showed equal susceptibility to immune meningitis. In contrast, male beta 2m-/- mice were less susceptible to fatal immune meningitis than were females. Orchidectomy and oestrogen treatment of male beta 2m-/- mice in vivo restored susceptibility to meningitis. The classic weight loss seen in beta 2m-/- mice after intracranial infection was also accentuated in females. Further, the in vitro activity of CD4+ T cells from male beta 2m-/- mice, as measured by CTL assays, was shown to be dependent on oestrogen. The natural killer cell activity of spleen cells from beta 2m-/- mice after infection with LCMV was not affected by oestrogen. These data demonstrate the influence of oestrogen on CD4+ T-cell activity both in vivo and in vitro.