Hyperacute rejection of a pig-to-primate organ xenograft is triggered by binding of anti-pig endothelial cell antibodies to the vascular endothelium of the xenograft and complement activation. Xenograft survival can be prolonged by pretransplant depletion of antibody with plasmapheresis or organ perfusion. However, these techniques have disadvantages for use immediately pretransplant or in the post-transplant period, including a marked reduction in coagulation proteins. To remove IgM and IgG from human plasma we employed a reusable Ig-binding column containing polyclonal antihuman IgG (heavy chain- and light chain-specific) conjugated to Sepharose beads (Therasorb, Baxter Corp.). Human blood was separated into plasma and cell fractions. Column absorption of plasma followed by recombination of plasma and cell fractions in the perfusion system resulted in 90.5 and 86.0% reduction in total IgG and IgM, respectively, and in a 47.0 and 69.4% reduction in IgG and IgM anti-pig endothelial cell antibodies, respectively. When the cellular fraction was recombined with untreated plasma and used to perfuse pig hearts in an ex vivo perfusion system, there was rapid cessation of normal cardiac rhythm (25.2 ± 5.6 min) and intense deposition of Igs, complement proteins, and fibrin in the tissues. In contrast, perfusion with blood containing column-absorbed plasma was able to sustain cardiac function, with normal sinus rhythm maintained for 258 ± 48.1 min, without tissue deposition of IgM or complement proteins and minimal deposition of IgG. We conclude that column absorption can be used effectively to deplete plasma of anti-pig endothelial cell antibodies. This procedure may be an effective method to help prevent hyperacute rejection of a pig heart transplanted into a human recipient.