The role of B cells and antibody in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) remains controversial. We previously demonstrated that B cells are required for EAE to be induced by the 120‐amino acid extracellular domain of myelin oligodendrocyte glycoprotein (MOG). In the present study, the role of B cells in MOG‐induced EAE was further characterized. Passive transfer of activated B cells or serum from MOG‐primed wild‐type (WT) mice was found to reconstitute the ability for clinical and histological EAE to be induced in MOG‐immunized B cell‐deficient mice. MOG‐induced EAE did not occur with transfer of B cells that had been nonspecifically activated by lipopolysaccharide or isolated from naïve or myelin basic protein (MBP)‐primed WT mice. Likewise, MOG‐primed serum, but not naive serum or serum from MBP‐, Hen egg lysozyme‐, or MOG_35–55‐primed mice, led to EAE in B cell^–/– animals. While both MOG‐primed B cells and serum reconstituted the ability for disease induction, MOG‐primed serum was much more efficient, leading to clinical and histological EAE similar to that seen in the WT. Injection of MOG serum into healthy B cell^–/ mice 30 days after MOG immunization led to rapid appearance of clinical signs and CNS inflammation, indicating that an antigen‐specific factor is necessary for initiation of CNS inflammation,and not just demyelination. These data strongly suggest that MOG‐specific antibody is critical to the initiation of MOG‐induced murine EAE.