We have previously demonstrated that hyperacute rejection does not occur in a pig-to-newborn baboon heart transplant model, presumably because of low levels of cytotoxic antipig antibodies present in the serum of newborn baboons. Cytotoxic antipig antibodies are primarily directed to α-1, 3- galactosyl (α Gal) residues on endothelial cell surface structures Twenty- one full-term humans and 5 full-term baboons were tested for complement mediated lysis (CML) of pig kidney (PK-15) cells and anti-α Gal activity with an ELISA using BSA-conjugated α Gal residues as target. To evaluate the significance of the anti-α Gal titers in vivo 5 newborn baboons underwent heterotopic pig cardiac xenotransplantation. Six of 21 human samples and 1 of 5 baboon samples demonstrated significant cytotoxicity to PK-15 cells. Twelve of 21 newborn humans had anti-α Gal IgG antibodies at titers of 1:80 or greater. None of the samples had anti-α Gal IgM. In newborn baboons, 1 of 5 sera had anti-α Gal IgG antibodies at titers greater than 1:80 and none of these samples had anti-α Gal IgM. Xenografts survived for an average of 3.6 days, even in the baboon with high anti-α Gal IgG titers. Analysis of the explanted grafts showed minimal evidence of complement-mediated hyperacute rejection (HAR), but prominent mononuclear cell infiltrates. In serum tested posttransplant there was an induced anti-α Gal response with cytotoxicity against PK-15 cells. These results show that anti-α Gal IgM is absent in newborn human and baboon sera, allowing pig grafts to avoid HAR. However, the presence of anti-α Gal IgG may be associated with mononuclear cell infiltration of the xenograft and its subsequent rejection.