In previous studies, we have shown that the oral administration of colonic proteins that have been haptenated (i.e., haptenated colonic proteins [HCPs]) with trinitrophenol (TNP) can protect mice from the subsequent induction of trinitrobenzene sulfonic acid colitis. Inasmuch as this protection was mediated by regulatory cells that express the antigen-non-specific suppressor factors transforming growth factor-β and interleukin-10, we reasoned that TNP-HCP feeding would also “cross-protect” mice from colitis induced by a different hapten, oxazolone. Indeed, we found that feeding TNP-HCP protected mice from the development of oxazolone-colitis, albeit to a lesser extent than it protected mice from trinitrobenzene sulfonic acid colitis. In addition, we showed that protection was associated with the appearance of mononuclear cells producing regulatory cytokines. These data strongly imply that the cells induced by feeding 1 type of haptenated protein are capable of cross-reacting with antigens present in colitis produced by a second type of haptenated protein. The cross-protection demonstrated in this study holds promise for the treatment of humans with inflammatory bowel disease because it shows that an appropriate fed antigen can induce regulatory cells that have the potential to suppress an inflammation induced by the unknown antigens causing this disease.