The immunosuppressive effect of splenectomy, alone or in combination with cyclosporine (CsA), was examined in hamster-to-rat orthotopic liver xenografts. The mean survival time was 7.3 +/- 0.5 days in untreated controls, 7.6 +/- 0.8 days with 40 mg/kg/day CsA, 7.2 +/- 0.4 days with splenectomy alone, and 17.6 +/- 5.6 days with splenectomy combined with 30 mg/kg/day CsA (P less than 0.01). The longest survival time was 27 days in this group. Marked enlargement of the spleen and high lymphocytotoxic antibody titer were characteristic of the unmodified recipients and those treated with CsA alone. Splenectomy by itself decreased the antibody formation without improvement of graft survival. In animals treated with the combined regimen, the lymphocytotoxic antibody titer was significantly suppressed, and the PMN and round cell infiltration were greatly reduced. Therefore, a synergistic effect was postulated between cyclosporine and splenectomy in this liver xenograft system.