NK1.1+ natural killer (NK)-T cells reactive to CD1 appear to be involved in spontaneous autoimmune disease, but their role in induced autoimmune disease remains unclear. While we previously reported a regulatory role of NK cells in experimental autoimmune encephalomyelitis (EAE), we demonstrate here that NK-T cells would also play a pivotal role in the control of EAE. C57BL/6 (B6) mice selectively depleted for NK-T cells were generated by antibody-depended protocols or knocking out TCRJα281 gene. Regardless of the method for NK-T cell deletion, these NK-T depleted mice developed unusually early onset of EAE (5–8 days after challenge) after immunization with an encephalitogenic peptide myelin oligodendrocyte glycoprotein (MOG) 35–55 . The early EAE onset was associated with early induction of T helper cell type 1 (Th1) cells and marked elevation of Th1 cytokines in the serum. It was of note that, although the NK-T deficient mice spontaneously recovered from EAE, mice selectively depleted for NK cells developed a later onset of non-remitting EAE. These data establish differential roles played by NK-T and NK cells in the protection against EAE.