Hepatic transplantation into humorally presensitized patients has occasionally been performed without reported accelerated rejection. To study survival of orthotopic hepatic transplants in sensitized recipients a series of studies in rats were performed. Lewis rats sensitized by three successive skin grafts from fully allogeneic ACI strain donors then underwent orthotopic hepatic transplantation from ACI donors. Nine of ten recipients died within 4 hr with bleeding from the liver surface. By comparison, nine unsensitized recipients survived a mean of 10.7 +/- 0.5 days before succumbing with cellular rejection. Death of the sensitized recipients was not due to coagulopathy or technical failure. Histological studies of hyperacutely rejected livers demonstrated marked hemorrhage, edema, congestion, and necrosis within the hepatic parenchyma. There was a relative lack of cellular infiltrate compared with livers rejected by unsensitized recipients. Immunofluorescent staining showed IgG bound to perivascular tissues and sinusoids, and complement bound to perivascular tissue. Serum from presensitized, but not control, recipients showed a high titer of donor-specific, complement-dependent cytotoxic activity. It is concluded that hyperacute rejection of hepatic transplants can occur in sensitized rats and is mediated by a humoral mechanism. The immunohistopathology of this process is described.