Summary: The cause of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), is unknown. Competing theories con- tend that disease is a T-cell–mediated autoimmune response against myelin antigens, infectious, or a virus- triggered immunopathology directed against one or more autoantigens. Clues to the nature of disease may lie in the presence of bands of oligoclonal IgG (OCBs) in MS brain and cerebrospinal fluid (CSF). OCBs are not unique to MS, and among other CNS diseases with intrathecal IgG synthesis and OCBs, all are inflammatory and most are infectious. Importantly, the CSF oligoclonal IgG in these CNS diseases is directed against the causative agent of disease, which provides a rationale for our hypothesis that the OCBs in MS are directed against disease-relevant antigen(s).1 Despite numerous studies, the specificity of oligoclonal IgG in MS CSF remains unknown.