Several hematopoietic cytokines have been investigated for their potential to provide protection from the lethal consequences of bone marrow aplasia after total body irradiation (TBI). Some can increase the dose of irradiation tolerated by the animals; none allow endogenous recovery after doses such as administered in clinical blood or marrow transplantation. We tested the radioprotective potential of FLT-3 ligand, an early acting hematopoietic cytokine, alone and in combination with a late acting cytokine, granulocyte-colony stimulating factor (G-CSF). Adult outbred New Zealand White rabbits were submitted to TBI of 1,200 or 1,400 cGy by a Co60 source. Recombinant human (rh) FLT-3 ligand at a dose of 500 microg/kg and/or rhG-CSF at a dose of 10 microg/kg were administered for 14 days subcutaneously daily, beginning either 2 days before or the day after TBI. All control animals given no growth factors died of aplasia at day 10 (range, 5 to 16). All 8 animals given G-CSF had severe aplasia and 7 died at day 8 (range, 5 to 10); 1 animal survived, with G-CSF being administered before TBI. In contrast, 11 of 12 animals given FLT-3 ligand, with or without G-CSF, survived. Radioprotection was best in the group given FLT-3 ligand together with G-CSF before TBI. In these animals median platelet counts were never <10 x 10(9)/L and median white blood cell counts never <0.5 x 10(9)/L. These data show that hematopoietic recovery can occur after 1,400 cGy TBI in rabbits, if protected by FLT-3 ligand, and suggest a radioprotective clinical potential of this cytokine.