Calcitonin gene-related peptide (CALCB), amylin, and adrenomedullin (ADM) belong to a unique group of calcitonin (CALCA)/CALCB family peptides that have overlapping biological effects owing to their structure and cross-reactivity between receptors. CALCB and ADM are expressed in fetoplacental tissues and are important in maintaining normal placental function. Recently, ADM 2 (ADM2)/intermedin was identified as a novel CALCA/CALCB family peptide that functions through CALCB and ADM receptors. ADM2 is expressed in the pituitary, digestive tract, and other organs of vertebrates and reduces blood pressure in both normal and hypertensive rats. We recently reported that the level of immunoreactive ADM2 is significantly upregulated in pregnant rats and that its hypotensive effects are also increased during rat pregnancy. Furthermore, infusion of ADM2 antagonist in pregnant rats causes fetoplacental growth restriction. The objective of this study was to analyze the expression and possible role of ADM2 in human placenta. We show that ADM2 mRNA is expressed in human placenta and that immunoreactive ADM2 is localized in syncytiotrophoblasts, cytotrophoblasts, and endothelial cells throughout human pregnancy. This study also demonstrates that ADM2 enhances the invasion and migration of first-trimester HTR-8SV/neo cells. ADM2 increases the invasive index of HTR-8SV/neo cells by 2.2-fold compared with controls. Taken together, the findings from this study suggest that ADM2 may have a role in the physiology of human pregnancy via regulation of trophoblast invasion and migration.