Background: Natural anti-Gal antibodies (NAb) to Gal epitopes play a key role in the rejection of pig cells or organs transplanted into primates. We have investigated the effect on NAb return after extracorporeal immunoadsorption (EIA) of the continuous intravenous (i.v.) infusion of (i) bovine serum albumin conjugated to Gal type 6 oligosaccharides (BSA-Gal) or (ii) a poly L-lysine backbone conjugated to Gal type 2 or 6 oligosaccharides (PLL-Gal). Methods: Porcine mobilized peripheral blood progenitor cells (PBPC) obtained by leukapheresis from MHC-inbred miniature swine (n = 9) were infused intravenously (i.v.) into baboons: Group 1 baboons (n = 4) received whole body and thymic irradiation, splenectomy, antithymocyte globulin, cobra venom factor, cyclosporine, mycophenolate mofetil, anti-CD154mAb, porcine hematopoietic growth factors, and EIA before transplantation of high doses (2 to 4 × 1010 cells/kg) of PBPC; Group 2 baboons (n = 3) received the Group 1 regimen plus a continuous i.v. infusion of BSA-Gal for up to 30 days; Group 3 baboons (n = 5) received the Group 1 regimen plus a continuous i.v. infusion of PLL-Gal type 2 (n = 2) or both PLL-Gal types 2 and 6 (n = 3) for up to 30 days. Results: Group 1: NAb returned to pre-PBPC levels within 20-30 days, but there was no induction of antibody to Gal or non-Gal determinants; Group 2: NAb was undetectable or at very low level during BSA-Gal therapy. In one baboon, however, IgG to Gal type 2, but not to type 6, returned during BSA-Gal therapy; Group 3: NAb was undetectable or at very low level during PLL-Gal therapy. In two baboons that received PLL-Gal type 2, NAb to Gal type 6, but not to type 2, returned during PLL-Gal treatment. Two of five baboons, however, developed systemic infection. Four of five baboons died within 14 days; autopsy revealed focal hemorrhagic injury to their hearts, lungs, and small intestines, with histologic abnormalities that varied between animals from hemorrhage and/or thrombosis in some organs (heart, lungs, or intestine) to signs of infections (bacteria in intestine, cytomegalovirus in liver). Conclusions: (i) BSA-Gal and PLL-Gal therapy maintained depletion of NAb. (ii) Some heterogeneity in specificity of NAb was identified, indicating that the infusion of a combination of Gal type 2 and 6 glycoconjugates may be required. (iii) The addition of PLL-Gal to the immunosuppressive regimen was associated with a high incidence of morbidity and mortality without a clear histopathologic entity underlying the cause of death.