The erythropoietin receptor (EpoR), known for its role in the proliferation and differentiation of erythroid cells, has been detected in nonhematopoietic tissues. We have reported previously that in addition to hematopoietic expression, EpoR is expressed at high levels in embryonic mouse brain and decreased to nondetectable levels by birth. While using transgenic mice to characterize human EpoR expression, we observed that a 15-kb human EpoR transgene (expressed in hematopoietic tissues but at a reduced level) also exhibited in the embryonic brain low levels of expression that persisted through adulthood. To examine further the basis of tissue and developmental specificity of the human EpoR gene, we produced additional transgenic mice using an 80-kb human EpoR genomic fragment isolated from a P1 phagemid human library. We found that this transgene is expressed appropriately in hematopoietic tissues (including yolk sac, fetal liver, adult spleen, and bone marrow) at levels comparable to the endogenous murine EpoR. The 80-kb transgene also provided high-level expression in the embryonic brain that paralleled the levels of the endogenous murine EpoR and was no longer detectable after birth. These data suggest that the high level of embryonic brain expression may be relevant to the human EpoR gene and that the transgenic mouse with an 80-kb fragment is a suitable model for studying the regulation and possible functional importance of human EpoR expression in the developing embryo.