The epidermal growth factor receptor (EGFR) and related family members (ERBB2, ERBB3, and ERBB4) previously have been shown to play pivotal roles in the development of female reproductive tissues, in blastocyst implantation, and in placental differentiation. We have cloned and sequenced several naturally occurring alternative transcripts of the human and mouse EGFR genes, which encode novel receptor isoforms containing varying portions of the extracellular ligand-binding domain, but lacking the transmembrane and cytoplasmic domain sequences. The human 1.8-kb and 3-kb alternative EGFR transcripts encode secreted 60-kDa and cell surface-associated 110-kDa EGFR isoforms, respectively. We have developed quantitative ribonuclease protection assays to study the expression of these alternative transcripts in human tissues. Similar to the full-length EGFR mRNAs, the highest expression level of these alternative transcripts occurs in placenta. We speculate that both of these EGFR isoforms may be important regulators of EGF-mediated cell growth and differentiation in human placenta.