We previously demonstrated the presence of erythropoietin receptors (Epo-R) on neurons in the developing human fetus (Peds Res, 40:376-380, 1996) but their function is unknown. A mechanism by which Epo promotes erythropoiesis is by decreasing apoptotic cell death of red cell precursers via the BCL2 and BLX pathways. Serum Epo concentrations increase with hypoxic stimuli, and neuronal Epo mRNA expression increases following hypoxia. We hypothesized that a physiologic role for Epo and Epo-R on human neurons involves protecting neurons from apoptotic cell death following hypoxia, using mechanisms similar to those utilized in the hematopoietic pathway. To test this hypothesis we first determined that Epo-R were present on NT2 cells and HNT cells, (a human neuronal cell line, and its mature neuronal counterpart) by RT-PCR. These cells were then incubated in 1% O2, 5% CO2, 94% N2 for 24, or 48 hours in the presence of rEpo (0 U/mL, 0.1 U/mL, 1.0 U/mL or 10 U/ml) followerd by 24 hours of normoxia. Evidence of apoptosis was determined by measurement of nuclear matrix proteins (NMP) from the conditioned media by ELISA. Nuclear matrix apparatus proteins are released into the media when cell death by occurs by apoptosis, but not by necrosis. Epo decreased the effect of hypoxia in a dose dependent manner in both NT2 cells and HNT cells at 24 and 48 hours. After 24 hours of hypoxia, NMP release by mature neurons incubated in the presence of 10 U/mL rEpo was reduced by 30%, to a level below that measured in normoxic controls. After 48 hours of hypoxia, NMP release by NT2 cells incubated with 1 U/mL rEpo was 43% the amount released by cells in hypoxia alone. We speculate that Epo-R expressed on human fetal neurons might constitute a previously undescribed physiologic mechanism for neuro-protection during fetal hypoximic episodes.