BACKGROUND We have demonstrated previously that the terminal complement component C6 contributes to the acute rejection of ACI cardiac allografts by PVG recipients. ACI rats differ from PVG rats at major and minor histocompatibility antigens and ACI cardiac allografts stimulate vigorous alloantibody responses in PVG rats. We have now bred the C6 deficiency onto four PVG congenic rat strains to determine the effects of C6 on cardiac allograft survival across individual donor-recipient major histocompatibility complex (MHC) disparities. METHODS Hearts from C6-deficient PVG.1A (RT1a) donors were transplanted heterotopically to fully MHC-incompatible C6-sufficient and C6-deficient PVG.1L (RT1(1)) recipients, as well as from C6-deficient PVG.R8 (RT1.AaBu) donors to MHC class I incompatible C6-sufficient and C6-deficient PVG. 1U (RT1.AuBu) recipients. RESULTS Hearts from PVG.1A (C6-) female donors were rejected acutely (7 to 9 days; n = 5) by fully MHC disparate female PVG.1L (C6+) recipients, but they survived significantly longer in female PVG.1L (C6-) recipients (13 to >50 days; n = 6). Slightly better survival resulted in male PVG.1L (C6-) heart transplant recipients of male PVG.1A (C6-) hearts (19 to >50 days [n = 5] vs 6 to 9 days for C6+ male PVG.1L recipients [n = 10]). The C6 deficiency had an even greater effect in PVG.1U recipients of class I MHC disparate PVG.R8 hearts (>50 day survival in C6- PVG.1U recipients [n = 5] vs 6 to 7 days in C6+ recipients [n = 8]). The cardiac allografts elicited similarly vigorous immunoglobulin M and G alloantibody responses in the C6- and C6+ recipients as measured by flow cytometry. At the time of acute rejection, the hearts in the C6+ recipients demonstrated extensive vascular endothelial destruction. In contrast, rejection of hearts by C6- recipients was characterized by endothelialitis, but there was little destruction of the endothelium and limited proliferation of smooth muscle cells in the intima. CONCLUSIONS These results demonstrate that the terminal complement component C6 can contribute to the rejection of class I or complete MHC-incompatible hearts in rats that have been characterized as "high" alloantibody responders.