We have tested the hypothesis that adrenomedullin (ADM), a multifunctional peptide hormone, works as a trophoblast proinvasion factor. Our results showed that ADM receptor components—the mRNA and proteins of calcitonin receptor-like receptor (CALCRL) and receptor activity modifying proteins (RAMPs)—were expressed by human choriocarcinoma JAr cells and first-trimester cytotrophoblast HTR-8/SV neo cells. ADM stimulates both JAr and HTR-8/SV neo cell proliferation. The invasion capabilities of JAr cells and HTR-8/SV neo cells were also enhanced by ADM, and this was associated with increased gelatinolytic activity and reduced plasminogen activator inhibitor-1 mRNA expression (SERPINE1). Our data support the notion that ADM may be involved in the human implantation process via regulating trophoblast proliferation and differentiation.