Non-obese diabetic (NOD) mice develop diabetes mediated by pathogenic T-helper type 1 (Th1) cells. V alpha 14 Natural killer (NKT) cells are a unique lymphocyte subtype implicated in the regulation of autoimmunity and a good source of protective Th2 cytokines. We recently developed a Th2-skewing NKT cell ligand, OCH. OCH, a sphingosine truncated derivative of alpha-galactosylceramide (alpha-GC), stimulates NKT cells to selectively produce Th2 cytokines. Here we show that OCH prevented the development of diabetes and insulitis in NOD mice. The suppression of insulitis by OCH was more profound compared to alpha-GC. Infiltration of T cells, B cells and macrophages into islets is inhibited in OCH-treated NOD mice. OCH-mediated suppression of diabetes is associated with Th2 bias of anti-islet antigen response and increased IL-10 producing cells among islet-infiltrating leukocytes. Considering the non-polymorphic and well conserved features of the CD1d molecule in mice and humans, these findings not only support the proposed role of NKT cells in the regulation of self-tolerance but also highlight the potential use of OCH for therapeutic intervention in type I diabetes.