Erythropoietin (Epo) is the physiologic regulator of erythrocyte production. Its actions are mediated through binding to specific cell surface receptors (Epo-R) which are expressed on erythroid progenitor cells. It is becoming clear, however, that Epo-R are not unique to erythroid progenitor cells, but are also expressed on certain non-erythroid, in fact, non-hematopoietic cell types. Recombinant Epo treatment is sometimes used to prevent or treat anemia in preterm neonates, but it is not clear what cell types, in human preterm infants, express Epo-R, and thus might be affected by rEpo administration. We therefore judged it necessary to determine the tissue distribution and cellular specificity of Epo and Epo-R in the organs of the developing human fetus. To accomplish this, tissue distribution panels(including: brain, spinal cord, eye, heart, lung, liver, spleen, adrenal, kidney, intestine, and placenta) were obtained from fetuses ranging in maturity from 5 to 24 weeks post conception. The presence or absence of Epo and Epo-R mRNA at 8 and 16 weeks post conception was established by RT-PCR, using specifically designed primer pairs. Immunohistochemical evidence of protein expression was then obtained using specific anti-Epo and anti Epo-R antibodies. mRNA for Epo and Epo-R was found in all organs at 8 and 16 weeks post conception, by RT-PCR. The cellular localization of Epo was, however, limited to the liver parenchymal cells, kidney interstitial cells and proximal tubules, neural retina of the eye, brain, and adrenal cortex. As development progressed, immunoreactivity in the kidney became more prominent. In contrast, immunoreactivity for Epo-R was widespread throughout the body, in cell types including endothelial cells, myocardiocytes, retinal cells, brain, cells of the adrenal cortex and medulla, as well as in small bowel, spleen, liver, kidney, and lung. We conclude that the distribution of Epo and its receptor is more widespread in the developing human than was initially postulated. The Epo receptor is expressed on many cell types during early fetal development, leading us to speculate that Epo acts in concert with somatic growth and development factors during this period. Further investigation is required to understand the non-hematopoietic role of Epo during human development.