Anemia in cancer patients is associated with reduced quality of life and local failure after radiation treatment. However, the use of erythropoietin to correct cancer anemia and to improve radiation efficacy was disappointing. Erythropoietin-receptor signaling mainly acts via activation of STAT 5, but also crossactivates the antiapoptotic transcription factor NF-kappaB. This causes neuroprotection against oxidative stress and implies radioprotection. In order to investigate possible radioprotective effects of erythropoietin-receptor signaling, we used an in vitro model system employing HeLa TetOff cells, stably transfected with an expression vector for the erythropoietin-receptor gene. Using electrophoretic mobility shift assays, we could demonstrate strong activation of NF-kappaB by erythropoietin-receptor signaling in HeLa cells. Activation of NF-kappaB did not require degradation of IkappaBalpha and was not prevented by proteasome inhibition. Furthermore, stimulation with erythropoietin resulted in a 50% increased clonogenicity of erythropoietin-receptor-expressing cells but did not alter radiation sensitivity itself. As most human tumors express erythropoietin receptor, we advocate a restricted use erythropoietin to patients suffering from erythropoietin-receptor-expressing cancers.