The effect of intragastric administration of antigen on the development of a mucosal cell-mediated immune response has been examined in a mouse model. Feeding mice with picryl sulfonic acid (PSA) abrogated development of buccal delayed-type contact hypersensitivity (CS) responses upon buccal challenge with picryl chloride (PCl) in animals that had previously been sensitized in the oral mucosa. In contrast, such feeding had no effect on buccal CS reactivity in animals similarly challenged but sensitized at skin sites. Conversely, gastric administration of PSA suppressed PCl-induced skin CS reactivity in skin-sensitized animals but had no effect on skin CS reactivity in buccally sensitized mice. Enterically induced suppression of buccal mucosa CS reactivity was associated with marked reductions in the numbers of infiltrating CD 11b+ macrophages and CD4+ cells, and a virtual disappearance of CD8+ cells in buccal tissue specimens examined 24 h after local challenge. Thus, depending on the initial site of immune sensitization, oral antigens may also suppress mucosal T cell reactivity.