Alpha-1-antitrypsin (A1AT), a serine protease inhibitor has been shown to protect tissues under various inflammatory conditions from proteolytic damage. Meanwhile, intracellular A1AT accumulation induces endoplasmic reticulum (ER) stress. Several reports have identified A1AT as a hypertensive disorders of pregnancy (HDP) or preeclampsia-related protein. However, significance of A1AT in placental pathophysiology is not fully understood. This study was designed to characterize the expression and function of A1AT in addition to serine protease family HTRA1 in the placenta. The role of A1AT was assessed using RNA-seq analysis with A1AT-knockdownd trophoblast. A1AT was expressed immunohistochemically in trophoblasts as well as endometrial tissues, whereas HTRA1 was in trophoblast. A1AT knockdown increased inflammation-related factors including IL-6 and IL-8, and altered four members of HTRAs expression in trophoblast. In turn, A1AT overexpression increased the expression of HTRA1 and several ER stress markers such as ATF6. Treatment of tunicamycin or thapsigargin, ER stress inducers, increased HTRA1 expression. In vitro invasion assay revealed that A1AT and HTRA1 positively regulated the cell invasion. These results suggest that endogenous A1AT may regulate local inflammation in the placenta and HTRA1-induced cell invasion via the induction of ER stress. Imbalance of functional interaction between A1AT and ER stress at the maternal-fetal interface might be involved in the disorder of placental development.