ORAL administration of antigen is used to induce antigen-specific peripheral immune tolerance^1,2. As well as preventing systemic immune responses to ingested proteins³, oral tolerance to autoanti-gens has also been used to suppress autoimmune diseases in animals^4-10and humans^11,12. Both active suppression and clonal anergy are suggested to be mechanisms of oral tolerance, depending on the dose of antigen fed^13,14. 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)-β and interleukin (IL)-4 and IL-10 cytokines. At higher doses, both Thl and Th2 cells were deleted following their initial activation, whereas cells which secrete TGF-β 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.