Insulin-regulated aminopeptidase (IRAP) activity increases during placentation and in the invasive tumor cell of trophoblast suggesting a role for this peptidase in the invasiveness of normal and malignant trophoblast. To investigate this hypothesis, we studied the effects of substrate (OT) and inhibitors (angiotensin peptides and LVV-H7) of IRAP on the first trimester trophoblast proliferation and invasion. Addition of these peptides in the culture medium of trophoblastic cells significantly decreased metalloproteinase-9 activity and cellular invasiveness while no effect was observed on cell proliferation. The peptide IRAP inhibitors could exert their effect on cytotrophoblastic cell invasiveness by inhibition of its enzymatic activity, and thus increasing half life of the known placental peptide substrate of IRAP, OT.