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Hamster to rat cardiac xenografts undergo delayed rejection as compared with the hyperacute rejection of discordant xenografts. Elicited xenoreactive Abs (EXA) are thought to initiate hamster to rat cardiac xenograft rejection, In this study, ne demonstrate that following transplantation of a hamster heart, rats generated high levels of ESA, Adoptive transfer into naive recipients of purified IgM, IgG2b, or IgG2c, but not IgG1 or IgG2a EXA, induced xenograft rejection in a complement-dependent manner. Ability of EXA to cause rejection correlated with complement activation, platelet aggregation, and P-selectin expression in the xenograft endothelium, Cyclosporin A (CyA) administration, after transplantation, totally suppressed IgG1, IgG2a, IgG2b, and IgG2c EXA, and inhibited IgM ESA production, but failed to overcome rejection, Administration of cobra venom factor (CVF), 1 day before and at the time of transplantation, resulted in complement inhibition during 3 days after transplantation, which failed to overcome rejection, Combination of CSA and CVF, which we have previously shown to overcome rejection, resulted in suppr ession of IgG EXA production and in the return of IgM SNA to preimmunization serum levels, 3 to 7 days after xenotransplantation, while complement remained inhibited, Thus, under CgA/CVF treatment, complement activation by hamster cells was suppressed following xenotransplantation and presumably for this reason xenograft rejection did not occur, In conclusion, our data demonstrate that EXA play a pivotal role in the pathogenesis of xenograft rejection and that CyA and CVF suppress xenograft rejection by preventing exposure of xenograft endothelial cells to complement activation by EXA.