Mast cell-deficient mice (W/W v) exhibit significantly reduced severity of experimental allergic encephalomyelitis (EAE), a murine model of multiple sclerosis. In this study, the contribution of FcR-mediated mast cell activation to disease was examined. W/W v mice were reconstituted iv with bone marrow-derived mast cells (BMMCs) from wild-type mice or those lacking functional FcRs. Eight weeks later, EAE was induced by immunization with the myelin oligodendrocyte glycoprotein 35–55 peptide. Disease scores were analyzed in reconstituted mice and compared with age-matched W/W v mice and wild-type littermates. Mice reconstituted with FcRγ−/− BMMCs or FcγRIII−/− BMMCs exhibited less severe clinical symptoms similar to W/W v controls, while reconstitution with FcRIIB−/− BMMCs resulted in disease significantly more severe than wild-type controls. Notably, mice reconstituted with FcγRIII−/− BMMC exhibit a relapsing-remitting course of disease. These data demonstrate that both activating and inhibitory FcRs expressed on mast cells influence the course of EAE.