Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide produced by tissue-specific alternative splicing of the primary transcript of the calcitonin gene. The objectives of this study were: 1) to determine the expression of CGRP and its receptor at the human implantation site, and 2) to examine the possible in vitro effect of this neuropeptide on two major partners of implantation, decidual cells and extravillous cytotrophoblasts. Immunohistological analysis of first-trimester placental chorionic villi showed CGRP in decidual cells and glandular cells, but not in extravillous trophoblast cells. CGRP expression was confirmed in cultured decidual cells by Southern blot analysis and immunocytochemistry and by RIA in culture medium. Transcripts of calcitonin receptor-like receptor were detected by Southern blot analysis of RT-PCR amplicons from both decidual and extravillous trophoblast cells, whereas transcripts for the receptor activity-modifying protein 1 were detected in decidual cells only. In vitro, CGRP stimulated cAMP production but not nitric oxide (NO) release by cultured decidual cells; in contrast CGRP increased NO release but not cAMP production in cultured extravillous trophoblasts. The presence of NO synthase (endothelial and inducible) was confirmed by immunodetection in extravillous trophoblasts, both in situ and in vitro. This study points to a paracrine and autocrine effect of CGRP on decidual and extravillous trophoblast cells, two major actors in implantation.