Multiple sclerosis (MS) occurs more commonly in females than males. However, the mechanisms resulting in gender differences in MS are unknown. Several studies have suggested that sex steroids influence the development and severity of MS. For example, pregnancy influences MS symptoms, with remission in the third trimester of gestation, followed by exacerbation in the postpartum period. In addition, oral contraceptives containing female sex steroids have been associated with a lower risk of developing MS and decreased disability. Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disorder initiated by T cells reactive against central nervous system (CNS) antigens. EAE is characterized by inflammation and demyelination of the CNS, and by remittent paralysis-features consistent with MS. Recent studies have suggested that female sex steroids may modulate EAE, at least in part, through effects on T cells. For example, sex steroids shift T cells toward a Th2 phenotype in vitro, and cytokines produced by Th2 cells generally suppress EAE. Activated microglia also are believed to contribute to MS pathology; perhaps due in part to production of nitric oxide (NO) and TNF-alpha, molecules which can be toxic to CNS cells, including oligodendrocytes. We are currently investigating the role of sex steroids in modulating microglial cell function in relation to MS. It is hoped that elucidation of the mechanisms by which sex steroids modulate CNS inflammation will lead to future therapies in the treatment of MS.