Epstein-Barr virus (EBV) infection results in a life-long persistence of the virus in the host's B-lymphocytes and has been associated with numerous cancers including Burkitt's lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. There is considerable evidence that EBV infection is a strong risk factor for the development of multiple sclerosis. Early age at primary EBV infection is typically asymptomatic, but primary infection during adolescence or adulthood often manifests as infectious mononucleosis, which has been associated with a two- to threefold increased risk of MS. Most importantly, MS risk is extremely low in individuals who are EBV negative, but it increases several folds following EBV infection. Additional evidence supporting a role for EBV in MS pathogenesis includes the observations of elevated antibodies to EBV antigens (especially EBV nuclear antigen-1) prior to the onset of MS, and an increased risk of MS among EBV-positive children. The biological mechanism by which EBV may cause MS is not known, but several possibilities are discussed.