The hormone erythropoietin is necessary for the maintenance, generation, and maturation of erythroid cells. This kidney-derived glycoprotein binds to cell-surface receptors, mediating both the proliferation and differentiation of erythroid cells. We have characterized 16 human erythropoietin receptor cDNA clones from two cDNA libraries prepared from OCIM1 poly(A)-containing mRNA. Of these 16 isolates, many showed evidence of incorrect RNA splicing events; others contained small deletions yielding multiple transcripts that may play a role in their erythroleukemic state. The human erythropoietin receptor, as deduced from the sequence of these clones, encodes a 508-amino-acid molecule, including a 24-residue signal peptide, a 226-amino-acid external domain, a transmembrane spanning region of 22 amino acids, and a cytoplasmic domain of 236 amino acids. There is an 80% overall homology between the human and murine erythropoietin receptor sequences.