We have previously identified the presence of Epo and its receptor in the human fetal CNS, and reported that pharmacologic doses of rEpo decrease hypoxia-induced apoptosis in human neuronal precursor cells (NT2). We now describe specific changes in the cellular distribution of Epo and Epo-R during neurodevelopment. We also report that physiologic concentrations of rEpo protect NT2 cells from UV-induced apoptosis. Two antibodies against human Epo-R, and Epo were used to identify immunoreactive cells in brains at 5, 10, 20, 24, 28, 32 weeks post conception, and in adult brains. The specificity of antibody reactions were checked by Western analysis. Controls for immunohistochemistry included specific and non-specific blocking peptides, absence of primary antibody, and substitution of pre-immune serum for specific antibody. At 5 weeks gestation, anti-Epo and Epo-R antibodies were both immunoreactive in the ventricular zone, while at 10 weeks only Epo staining was prominent in the ventricular zone, with Epo-R staining primarily the subventricular zone. Both antibodies stained the cortical plate. As development progressed, Epo reactivity became most prominent in neurons, although a subpopulation of astrocytes were also immunoreactive. This was in contrast to Epo-R staining, which was most prominent in astrocytes, although weak immunoreactivity was also present on neurons. To test the hypothesis that Epo is neuroprotective at physiologic doses, we pretreated NT2 cells for 16 hrs with either 50mU/mL rEpo, 50mU/mL rEpo+neutralizing antibody, or PBS(n=8). Cells were exposed to 11 sec UV irradiation (vs no UV control). After 16 hrs, cells were stained with trypan blue and counted, and nuclear matrix protein (NMP) released into the media was measured by ELISA. Cells exposed to 50 mU/mL Epo were rescued from UV-induced apoptotic cell death, as evaluated by both cell counts and decreased NMP (p<0.05). We have previously documented Epo concentration in neonatal CSF as high as 68 mU/mL, thus 50 mU/mL is within the physiologic range. We conclude that Epo and its receptor are present within the developing human brain, that the pattern of distribution of these proteins change with development, and that inhibiting apoptotic cell death may be one function of this cytokine-ligand pair.