The antibody responses to ingested antigens are normally enhanced following a portacaval shunt (PCS), but the cell-mediated immune response has not been examined. It is also known that prior feeding induces tolerance to soluble protein antigens. This study examines the effect of PCS on oral cell-mediated tolerance. Normal Lewis rats (n = 16) and those (n = 10) with an end-to-side portacaval shunt surgically created 7 days earlier were fed either 200 mg soluble ovalbumin (OVA) or water by daily gastric gavage for 7 days. One week later, all animals were challenged subcutaneously with 250 μg OVA admixed in complete Freund's adjuvant. Twenty-one days later, delayed-hypersensitivity (DTH) responses were measured 24 hr after injection of 100 μg OVA (in media), or an irrelevant antigen (SRBCs), into the pinna of the ear. The intensity of the response was reflected by the increment in ear thickness, as well as the histological intensity of the mononuclear cell infiltrate. Oral administration of OVA significantly and specifically abrogated the DTH response to subsequent challenge with OVA (P < 0.001). This DTH hyporesponsiveness was significantly reversed by the creation of a PCS (P < 0.001). We conclude that the initial processing of ingested antigen within the liver is essential for the development of oral cell-mediated immune tolerance.