Background & Aims: Defective suppressor/regulatory T-cell activation has been proposed as a mechanism to explain the uncontrolled inflammatory process seen in inflammatory bowel disease (IBD). Previous studies have suggested that inappropriate activation of CD4+ T cells may occur in the gastrointestinal tract in these patients. Because suppressor/regulatory T cells are thought to be one mechanism for the promotion of oral tolerance, we attempted to induce tolerance in normal controls (n = 21) and patients with either Crohn's disease (CD, n = 12) or ulcerative colitis (UC, n = 13). Methods: Subjects were fed keyhole limpet hemocyanin (KLH) before subcutaneous immunization and booster immunization. Blood for KLH-induced T-cell proliferation and serum for anti-KLH antibody was obtained at baseline and after feeding, immunization, and booster. Results: In the control group, KLH feeding (50 and 250 mg) before immunization and booster resulted in reduced KLH-specific T-cell proliferation compared with the group that was not fed KLH (P < 0.002). However, both CD and UC patients showed significantly enhanced proliferation, without tolerance induction, when compared with baseline values (P < 0.035 and 0.02, respectively). Serum antibody to KLH was present only after immunization in the control group; however, anti-KLH antibody was seen after oral administration in both the UC and CD groups. Conclusions: Taken together, these data suggest that oral antigen administration does not result in tolerance in CD and UC patients, and might actually result in active immunity. This may reflect an in vivo functional defect in mucosal suppression of immune responses in IBD.