Experimental autoimmune encephalomyelitis (EAE) is a prototype autoimmune disease mediated by type 1 helper T (TH1) cells and under the control of regulatory cells. Here we report that a synthetic glycolipid ligand for CD1d-restricted natural killer T (NKT) cells expressing the semi-invariant T-cell receptor (Valpha14+) is preventive against EAE. The ligand is an analogue of alpha-galactosylceramide (alpha-GC), a prototype NKT cell ligand, with a truncated sphingosine chain. alpha-GC causes NKT cells to produce both interferon (IFN)-gamma and interleukin (IL)-4 (refs 4, 5). However, this new ligand can induce a predominant production of IL-4 by the NKT cells. A single injection of this glycolipid, but not of alpha-GC, consistently induced TH2 bias of autoimmune T cells by causing NKT cells to produce IL-4, leading to suppression of EAE. The lack of polymorphism of CD1d and cross-reactive response of mouse and human NKT cells to the same ligand indicates that targeting NKT cells with this ligand may be an attractive means for intervening in human autoimmune diseases such as multiple sclerosis.