The molecular bases responsible for the loss of T cell tolerance to myelin antigens leading to the onset of multiple sclerosis remain obscure. It has been shown that balanced signaling through activating and inhibitory receptors is critical for the maintenance of tolerance to self antigens in autoimmune disorders. However, although FcgammaR have been shown to influence experimental autoimmune encephalomyelitis (EAE) development, their role during pathogenesis remains controversial. Here we have evaluated whether relative expression of activating (FcgammaRIII) and inhibitory (FcgammaRIIb) FcgammaR can modulate myelin-specific T cell response, as well as the susceptibility to develop EAE in mice. While FcgammaRIIb(-/-) mice showed a significant increase in EAE severity, an FcgammaRIII deficiency protected mice from disease. In addition, FcgammaRIIb(-/-) mice showed enhanced activation of myelin-specific effector T cells, which were significantly more effective at causing EAE in adoptive transfer experiments than were T cells from wild-type mice. In contrast, FcgammaRIII(-/-) mice showed a significantly reduced activation of myelin-specific T cells and these cells failed to adoptively transfer EAE. Consistently, increased expansion of regulatory T cells (Treg) during EAE was observed only for FcgammaRIII(-/-) mice, which were able to suppress disease when adoptively transferred to recipient mice. These findings suggest that the balance between activating and inhibitory FcgammaR signaling can contribute to the maintenance of T cell tolerance to myelin antigens and modulate EAE progression.