Orally administered antigens can induce systemic tolerance. In animal models, oral tolerance can both prevent and treat experimental autoimmune diseases. The induction of oral tolerance to human autoantigens has been envisioned as a potential treatment for human autoimmune conditions. The results of previous human studies from our laboratory have provided evidence that oral administration of a model antigen, keyhole limpet hemocyanin (KLH), prior to systemic immunization, can decrease the magnitude of subsequent T cell proliferative and skin test responses to KLH. The present study was designed to test the hypothesis that orally administered KLH could attenuate a preexisting immune response to KLH. Thus, human subjects (n = 8) were primed subcutaneously with KLH without adjuvant prior to a 42-day feeding regimen of 100 mg of KLH per day. At the end of the feeding regimen, the subjects were boosted with KLH, again without adjuvant. Eight control subjects were immunized as above with KLH, but fed ovalbumin. The measurement of antigen-driven T cell proliferation, serum and salivary antibody, and dermal delayed hypersensitivity responses to KLH failed to reveal significant differences between subjects fed KLH and those fed ovalbumin. These results indicate that the KLH dose and feeding regimen used in this study failed to attenuate the primary response or to prevent the secondary response to KLH. Therefore, some form of immunomodulation greater than that provided by oral administration of antigen alone is required in humans for suppression of an existing immune response. © 2004 New York Academy of Sciences.