The enhancement of protective mucosal responses to infectious agents sought by vaccinologists, and the desired suppression of immune responses to autoantigens, allergens and food antigens induced by mucosal exposure to relevant antigens, may seem paradoxical. However, such outcomes are not mutually exclusive because of a hierarchy in the quality of immune responses: mucosal immunity manifested by the appearance of secretory antibodies and systemic tolerance manifested by diminished cell-mediated responses may be induced concomitantly. We have demonstrated that the ingestion, or nasal application, of a neo-antigen-keyhole limpet hemocyanin (KLH)-primes human volunteers for subsequent humoral mucosal and systemic responses induced by systemic immunization but suppresses cell-mediated responses (T cell proliferation and delayed-type hypersensitivity). Furthermore, extended ingestion of selected food antigens diminished, but did not totally suppress, cell-mediated immunity and levels of serum antibodies while salivary antibodies were easily detectable. Most importantly, the humoral and cellular immune responses induced by systemic immunization with KLH could not be suppressed by subsequent extended ingestion of large doses of the same antigen. Thus, ongoing systemic responses are refractory to the induction of mucosal tolerance in humans. This finding is of considerable importance for the development of and sequence of immunization with mucosally administered vaccines. © 2004 Elsevier Ltd. All rights reserved.