The aim of this study was to determine the mechanisms responsible for concordant xenograft rejection using the hamster-to-rat heart graft model. Even though it was known that rat CD4 positive T cells proliferated to hamster stimulators in mixed lymphocyte reactions, the depletion of CD4 positive T cells in rat recipients did not lead to an extension of xenograft survival. Suppression of T cell immunity using other monoclonal antibodies or cyclosporine also failed to improve survival. Only by depleting complement with cobra-venom factor could hamster xenograft survival be prolonged, and long-term survival was achieved by combining CsA with COF. High-antibody titers to hamster cells were found after transplantation of hamster hearts, and evidence is presented that rejection of these "concordant" xenografts is mediated primarily by antibody-complement mechanisms. The antihamster antibodies were produced in the absence of T cell help, which suggests that antibody-mediated graft destruction cannot be inhibited by suppression or depletion of T cells. Pharmacologic depletion of complement for the clinical application of concordant xenografts is a promising avenue of future research.