Renal heterotransplant rejection was studied in the dog and pig, an experimental model representing widely divergent phylogenetic species. Whole organ heterograft rejection in these species was characterized by an immediate reaction (pig to dog 10–20 min and dog to pig 2–4 hours) manifested grossly and histologically by congestion, endothelial destruction and hemorrhage. In this model the mechanism responsible for the immediate vascular rejection process was demonstrated to be preformed cytotoxic antibody. Analysis of complement depression following heterotransplantation suggested the possibility of 2 components of rejection, the first directed against red cell antigens and the second against tissue antigens. The pattern of heterograft rejection was not altered by: (1) differences in blood types of the heterotransplanted animals; (2) qualitative differences in erythrocyte cross-matched results; (3) antibody absorption in vivo; (4) immunosuppressive drugs.