This work was undertaken to investigate the role of nonparenchymal liver cells in a discordant model of hepatic xenografting. Three experimental groups were established: in group 1 guinea pig to Lew rat liver xenotrans-plantations were performed; in group 2 both donor and recipient were treated with dextran sulfate, a known inhibitor of the reticuloendothelial system phagocytic function; in group 3 both donor and recipient were injected with muramyl dipeptide, a synthetic immunomodulator stimulating the monocyte/macrophage axis. Survival time was assessed and xenoantibody titers 30 min before and after the intervention, Kupffer cell activity 30 min after transplantation, histology and immunoglobulin and complement deposits of the grafted liver were evaluated too. Survival time of the xenografted rats in group 1 was 6.4 ± 0.31 h. Blockade of Kupffer cells by dextran sulfate administration significantly (p < 0.001) depressed the survival time (2.9 ± 0.31 h) of the grafted rats, while a significant increase (p < 0.001) was observed in the muramyl dipeptide-treated group (9.3 ± 0.52 h). A significant reduction of xenoantibody titers 30 min after intervention was observed in the muramyl dipeptide group while no reduction was observed in the dextran group. Thirty minutes after xenotransplantation sheep red blood cell 51Cr uptake was significantly depressed by dextran sulfate treatment while muramyl dipeptide administration restored the Kupffer cell activity. Histological changes worsened after dextran administration in comparison with the other groups. Immunoglobulins and complement deposits were diminished by dextran administration. Our findings suggest that the increased ability of lining cells to clear preformed antibodies from the blood supply may be responsible, at least partially, for the prolonged survival observed in the muramyl-treated gro