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Placental development in mice involves highly regulated interactions between fetal- and maternal-derived cells. We have previously cloned a novel serine protease (HtrA3) containing an insulin-like growth factor (IGF) binding domain, which was upregulated during pregnancy, especially post-implantation in the mouse uterus.1 The present study examined HtrA3 regulation during placental development in mice, in particular, its expression in the different compartments of the placenta. Expression of mRNA was determined by Northern blot analysis in implantation units containing the decidua, placenta and fetus (day 8.5 to near-term). A specific HtrA3 antibody was generated, affinity-purified and used for Western blot analysis and immunohistochemistry. Both mRNA and protein of HtrA3 were identified specifically in the maternal decidua. In contrast, HtrA3 expression was below detection in trophoblasts, including the giant cells that are in direct contact with the decidua. This pattern persisted from the early stages of placentation to near term. The level of decidual HtrA3 mRNA and its protein gradually decreased as the placenta matured. In the decidua, only the maternal decidual cells, but not blood vessels or uterine NK cells that are present in large numbers, were positive for HtrA3. The specific localization of HtrA3, a protease possessing an IGF binding domain at the maternal–fetal interface, suggests that this protein plays an important role in mediating maternal decidual remodelling and maintenance, probably in association with the IGF system, in placental development and function. (1)Nie et al. (2003). Mol. Hum. Reprod.