The destructive action of alloantiserum and exogenous complement on ingrowing skin allografts was studied. B6AF1 recipients of a B10.D2 skin graft received a single intravenous injection of B6AF1 anti-B10.D2 serum (antiserum to H-2K.31) together with rabbit complement (RC) within the first 10 days after transplantation. Different models were used: recipients without immunosuppression, recipients treated with antilymphocyte serum, x-irradiation, or enhancing antibody. If the injection was given between day 5 and 10 after grafting, hyperacute rejection occurred in all cases. The rejection seemed to be most violent when the injection was given on days 7 or 8. Injections given on days 1, 2 or 3 after grafting could not induce hyperacute-rejection, but resulted, on the contrary, in a prolongation of graft survival, probably due to immunological enhancement. Injections on day 4 produced patchy necrosis, but the grafts recovered and the residual tissue showed a prolonged survival. The results suggest that the presence of a functioning vascular network is a prerequisite for the occurrence of hyperacute rejection of skin allografts in the mouse.