Oral administration of antigen is used to induce antigen-specific peripheral immune tolerance. As well as preventing systemic immune responses to ingested proteins, oral tolerance to autoantigens has also been used to suppress autoimmune diseases in animals and humans. Both active suppression and clonal anergy are suggested to be mechanisms of oral tolerance, depending on the dose of antigen fed. Here we report that oral antigen can delete antigen-reactive T cells in Peyer's patches, in mice transgenic for the ovalbumin-specific T-cell receptor genes. The deletion was mediated by apoptosis, and was dependent on dosage and frequency of feeding. At lower doses deletion was not observed; instead there was induction of antigen-specific cells that produced transforming growth factor (TGF)-beta and interleukin (IL)-4 and IL-10 cytokines. At higher doses, both Th1 and Th2 cells were deleted following their initial activation, whereas cells which secrete TGF-beta were resistant to deletion. These findings demonstrate that orally administered antigen can induce tolerance not only by active suppression and clonal anergy but by extrathymic deletion of antigen-reactive Th1 and Th2 cells.