The capacity of basic protein of myelin (BPM) from various species to produce experimental autoimmune encephalomyelitis (EAE) in the guinea pig or the Lewis rat, was abrogated by mixing BPM with alpha2 macroglobulin, transferrin, and ceruloplasmin. Inhibition of EAE was observed only when the encephalitogen was held in vitro directly with the inhibitor and not when each was injected separately. Guinea pigs which failed to develop EAE after an injection of a mixture of BPM with alpha2 macroglobulin nevertheless developed cell-mediated immunity and antibodies to BPM. However, animals injected with a mixture of the encephalitogenic tryptophan peptide of BPM with alpha2 macroglobulin developed neither cell-mediated immunity nor humoral antibody to BPM. Inhibition of EAE in the present studies was attributed to binding between the inhibitor and BPM, which possibly blocked its main encephalitogenic determinant, rather than enzymatic cleavage of BPM. This inhibitory effect of alpha globulin on immunogenicity could represent a further example of homeostatic control over immune responses.