C plays a critical role in the hyperacute rejection (HAR) of discordant xenografts (Xg), but the relative contribution of early vs late C components is unknown. In this study, genetic differences in C6 activity were correlated with HAR of guinea pig cardiac Xg by the rat. Seven rat strains were tested for C activity. Six strains (PVG.R1 (R1), PVG.1A (1A), DA, W/F, F344, LEW) had readily detectable C activity in the total and alternative pathways. Some PVG rats also had adequate C activity [PVG (C+)] but others [PVG (C-)] had a profound C6 deficiency. All rats with adequate C activity (n = 35) rejected cardiac Xg between 15 and 80 min. PVG (C+) (n = 6) rats also rejected cardiac Xg hyperacutely (26 +/- 12 min), whereas PVG (C-) (n = 16) rats, which had high preformed IgM natural antibody titers, rejected cardiac Xg in 1 to 2 days (2678 +/- 542 min). Transfer of serum from R1 rats to PVG (C-) recipients with vigorously beating Xg caused HAR of cardiac Xg within 116 +/- 75 min. Transfer of fresh PVG (C-) serum or heat-inactivated R1 serum did not induce HAR. HAR was characterized by intravascular platelet aggregation and interstitial hemorrhage, whereas Xg transplanted to PVG (C-) recipients had patent vessels at 30 min but were heavily infiltrated by granulocytes and monocytes at 2 days. These findings indicate that a deficiency in C6 prevents HAR but allows an accelerated acute rejection that may be mediated by the generation of vasoactive and chemotactic C3a and C5a.