Natural anti-carbohydrate antibodies are central to hyperacute rejection in ABO-incompatible allotransplantation and in discordant xenotransplantation. ABO-incompatible rejection has been inhibited successfully using intravenous soluble carbohydrates as antibody inhibitors. The approach has been less successful previously in pig to primate xenotransplantation, where the necessary concentrations of a partial inhibitor (Gal alpha 1-6Glc) proved highly toxic. In this study, we have identified more effective inhibitors of the dominant human anti-pig antibodies that bind to the pentasaccharide Gal alpha 1-3Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4Glc beta 1-. The inhibitors are the terminal disaccharide (Gal alpha 1-3Gal) and terminal trisaccharide (Gal alpha 1-3Gal beta 1-4GlcNAc) of the target pentasaccharide. Twelve sera (3 from each ABO blood group) were tested in 3 different assays: lymphocytotoxic, lymphocyte flow cytometry, and solid-phase antigen ELISA. Fifty percent to 75% inhibition of human IgG and IgM was achieved using the disaccharide and trisaccharide inhibitors in the range of 10-50 mM. Disaccharide (70 mM) was used to inhibit hyperacute thrombosis in pig kidneys perfused for 40 min with heparinized human AB whole blood. The disaccharide completely inhibited red cell occlusion of glomerular but not of intertubular capillaries, although there was residual platelet thrombus in glomeruli. Disaccharide and trisaccharide can, therefore, be used in concentrations shown for other carbohydrate inhibitors to be nontoxic, for inhibition of hyperacute pig-to-human xenograft rejection. The inhibition is incomplete, however, and other antigen specificities and other rejection mechanisms are likely to be involved.