Multiple sclerosis (MS) is simulated by various forms of experimental autoimmune encephalomyelitis, in which T cells, antibodies, cytokines and complementary factors interact with the central nervous system (CNS) myelin proteins and lead to inflammatory damage. We investigated the role of Fc receptors (FcRs), which link the cellular and humoral branches of the immune system, in myelin oligodendrocyte glycoprotein (MOG)‐induced experimental autoimmune encephalomyelitis (EAE), using two different FcRγ knockout DBA/1 mice. The first knockout were the FcRγ chain‐deficient mice, which lack FcγRI, FcγRIII and FcεRI, while the second knockout mice lack only FcγRII. The lack of FcγRII enhanced the disease susceptibility with associated increased CNS demyelination. While FcRγ^+/+ DBA/1 mice also developed pronounced CNS infiltration and myelin destruction, FcRγ^−/− littermates were protected despite initial peripheral autoimmune responses to MOG. In vitro analyses revealed equivalent potentials of fluid phase phagocytosis of myelin and MOG in bone‐marrow macrophages derived from both FcRγ^+/+ and FcRγ^−/− mice, while MOG‐immunoglobulin (Ig)G immune complexes were only internalized by FcRγ^+/+ macrophages. This was associated with cellular activation in FcRγ^+/+ but not FcRγ^−/− macrophages, as assessed by the activation of intracellular mitogen activated protein (MAP)‐kinase signalling elements. We propose that protection from EAE in FcRγ‐deficient mice is due to the inefficient antigen processing/presentation of myelin proteins during the induction of secondary immune responses locally in the CNS, which leads to demyelination. This demonstrates the importance of FcR in the promotion of autoimmune inflammation of the CNS and highlights the therapeutic possibility of treatment of MS with FcR‐directed modalities.