Amphiregulin (AR) is a growth regulatory glycoprotein with significant amino acid homology to members of the epidermal growth factor (EGF) family. Its effects are mediated via the EGF receptor tyrosine kinase or through specific nuclear targeting sequences. In this study, the localization of immunoreactive AR was examined in paraformaldehyde-glutaraldehyde fixed, paraffin-embedded human placentae and decidua obtained at various stages from 11 weeks to term pregnancy using the avidin-biotin complex/peroxidase method. In addition, the effects of AR on trophoblast proliferation were evaluated from 3HTdR uptake by first trimester human trophoblast cells. Results revealed immunolocalization of AR to the nucleus as well as the cytoplasm of the syncytiotrophoblast cell layer of chorionic villi until approximately week 18 of gestation after which no immunostaining was detected. Villous and extravillous cytotrophoblast cells as well as decidual tissue were negative for AR at all gestational ages examined. In the presence of exogenous AR, there was a dose-dependent increase in proliferation of the trophoblast at AR concentrations ranging from 1-100 ng/ml. These results suggest that AR may be an important paracrine or juxtacrine growth stimulatory molecule for cytotrophoblast cells in situ early in gestation.