The usual result of feeding protein antigens to naive animals is the induction of profound immunological unresponsiveness and this is currently being exploited to treat inflammatory disease. Because the most useful therapeutic application of feeding antigen would be to suppress established disease, the aim of this study was to compare the immunological basis of oral tolerance induced by feeding a model antigen to naive and primed animals. We show that feeding 2-200 mg ovalbumin (OVA) to mice 7 days after immunisation with OVA in adjuvant produces dose-dependent suppression of delayed-type hypersensitivity (DTH), T cell proliferation, and both TH1 and TH2 cytokines, although serum IgG levels were unaffected. Feeding OVA before immunisation suppressed all these responses. Although feeding up to 8 days after immunisation could suppress some subsequent responses, tolerance was induced much more effectively when antigen was fed in the first 4 days after immunisation. Tolerance in primed mice was intact in IL-4-/- mice, indicating that it was not caused by selective upregulation of TH2 cells in vivo. We conclude that oral administration of protein antigen can inhibit ongoing responses by all effector T cell subsets, but the exact consequences, and therefore possibly the mechanisms, are different from those induced by tolerising naive mice. These findings may have important implications for designing therapeutic regimes exploiting oral tolerance.