Multiple sclerosis (MS) is a chronic disabling autoimmune disease of the central nervous system (CNS). Cytomegalovirus (CMV), a beta herpes virus, may have a detrimental or beneficial role in MS pathology. Accumulating evidence indicates that CMV contributes to MS disease via interplay of different mechanisms such as molecular mimicry, bystander activation, and epitope spreading. The activation and expansion of a specific T cell subset, CD4(+)CD28(null)T cells, via CMV infection could also contribute to MS pathology. Various additional observations also indicate a protective effect of CMV on autoimmune diseases. CMV immune evasion may mitigate the autoimmune reactions and proinflammatory milieu that contribute to MS.