Oxazolone colitis (OC) is an experimental colitis that has a histologic resemblance to human ulcerative colitis. Here we show that IL-13 production is a significant pathologic factor in OC since its neutralization by IL-13Rα2-Fc administration prevents colitis. We further show that OC is mediated by NK-T cells since it can be induced neither in mice depleted of NK-T cells nor in mice that cannot present antigen to NK-T cells and mice lacking an NK-T cell-associated TCR. Finally, we show that NK-T cells are the source of the IL-13, since they produce IL-13 upon stimulation by α-galactosylceramide, an NK-T cell-specific antigen. These data thus describe a cellular mechanism underlying an experimental colitis that may explain the pathogenesis of ulcerative colitis.