It has been proposed that defective activation of suppressor or regulatory T cells is one mechanism involved in the uncontrolled inflammatory process seen in inflammatory bowel disease (IBD). Because suppressor/regulatory T cells are thought to play a role in the promotion of oral tolerance, we attempted to induce oral tolerance in normal controls (n = 21) and patients with either Crohn's disease (CD; n = 12) or ulcerative colitis (UC; n = 13). In the first study, subjects were fed the neoantigen keyhole limpet hemocyanin (KLH) on days 1 to 5 and 11 to 15. Subcutaneous immunization with KLH was performed on day 26, with a booster immunization on day 35. Blood for KLH-induced T cell proliferation and serum for anti-KLH antibody production was obtained at baseline, on day 26 preimmunization (postfed), on day 35 after the first immunization, and again on day 42 after the second immunization. In normal individuals, KLH feeding prior to immunization and booster resulted in reduced KLH-specific T cell proliferation compared with the group that was not fed KLH. However, although on the same KLH-feeding protocol, both CD and UC patients demonstrated significantly enhanced proliferation without oral tolerance induction when compared with baseline values. These data suggest that oral tolerance induction is defective in patients with IBD. This may reflect an in vivo functional defect in mucosal suppression of immune responses in IBD. Both UC and CD appear to be multigenic disorders with evidence of familial segregation. We analyzed four multiplex Crohn's and two UC families to determine whether the defect in tolerance induction was genetically regulated. In three of the four CD families at least one unaffected family member also failed to tolerate (total 5 of 14 unaffected family members). In the UC families, the defect in tolerance segregated with disease. These data suggest a genetic defect in tolerance induction in Crohn's disease.