The human monoclonal IgM antibody sHIgM22 and mouse IgM monoclonal antibody 94.03 bind to oligodendrocytes, induce calcium signals in cultured glial cells, and promote remyelination in mouse models of multiple sclerosis. In order to address the mechanisms employed by these antibodies to promote CNS repair, bivalent monomers, F(ab')2 fragments, and monovalent forms of these antibodies were investigated to determine whether they exhibit the same remyelinating potential as the intact IgMs. The two antibodies displayed different structural requirements for retention of function. Antibody sHIgM22 remained functional even when reduced to a bivalent F(ab')2 fragment, while disruption of the pentameric structure of antibody 94.03 destroyed its functional properties. Competition studies demonstrated that the two antibodies recognize different entities on the surface of glial cells. These results indicate that the constant region and pentameric structure of IgM is not always necessary for the stimulation of myelin repair, eliminating the requirement for IgM immune effector functions in this process. The ability of the antibodies to cross-link cell surface determinants on oligodendrocytes appears to be an essential aspect of the mechanism of cellular activation. The finding that two antibodies, which induce similar in vivo effects, bind to different structures, and have different cross-linking requirements suggests that activation of glial cells involves the rearrangement of a complex membrane compartment.