Oral tolerance induction has proven to be an effective approach for inducing antigen-specific unresponsiveness in several models for allogeneic transplantation and autoimmune diseases. The authors' preliminary studies, however, indicated that xenospecific antibodies are produced when rats are given mouse erythrocytes orally. This response was further examined. Mouse erythrocytes were administered to rats orally or intravenously during one or two episodes, and sera were obtained on day 9 or day 29, respectively. Rat sera containing a positive hemagglutinating titer against mouse antigens were injected into rats that had recently undergone xenotransplantation to study graft survival. Oral administration of xenogeneic cells induced a powerful antibody response consisting mainly of xenospecific immunoglobulin (Ig) M and IgG. This antibody response also induced hyperacute rejection as powerfully as sera from intravenously immunized rats. The authors' study thus indicates that oral administration of xenogeneic cells is a powerful immunization pathway that induces an antibody response capable of rejecting concordant vascularized xenografts.