Immune responses and the mechanisms of tolerance to the common dietary antigens bovine gamma globulin (BGG), ovalbumin (OVA), and soybean protein were evaluated in normal human volunteers. Humoral and T cell proliferative responses to these antigens were measurable but low, consistent with immune tolerance. There were limited correlations between responses in the systemic and mucosal compartments, and in general the responses to one dietary antigen could not predict the response to another. T cell proliferation to dietary antigens increased significantly by addition of recombinant human interleukin-2 (rhuIL-2). Peripheral blood mononuclear cells stimulated with BGG or OVA expressed IL-2Rα chain but not IL-2 mRNA, consistent with T cell anergy. Incubation with exogenous IL-2 alone did not restore T cell proliferation to BGG or OVA. In some individuals T cell proliferation to an unrelated vaccine antigen was suppressed by addition of BGG or OVA, but could be reversed with low doses of rhuIL-2. We conclude that in humans anergy is the major mechanism of tolerance to chronic antigen feeding, and we propose that such anergic, antigen-specific T cells actively contribute to maintenance of homeostasis in the intestine in the face of massive antigen challenge. © 2001 Academic Press.