The effect of recombinant rat interferon-gamma (rRIFN-gamma) on allograft rejection was studied in two rat heart transplantation models. Recipients were treated with rRIFN-gamma by intraperitoneal or intravenous injection, either by bolus or continuous infusion. Treatment was started after transplantation and continued during a period ranging from 4 to 10 days; dosages varied from 2.5 x 10(2) U/kg/day to 3 x 10(6) U/kg/day. Controls were infused with PBS. Treatment with rRIFN-gamma had no effect on allograft survival, irrespective of the route of administration, the dosage used or the duration of treatment. Higher dosages of rRIFN-gamma induced serious morbidity and mortality. In conclusion, systemic treatment of cardiac allograft recipients with rRIFN-gamma has no effect on graft rejection and is associated with serious toxicity and mortality when high dosages are used.