Background: Trophoblast invasion is regulated by trophoblast-decidual cell interaction. Results: HtrA1 and HtrA3 expression is up-regulated in decidualization stimuli-treated endometrial cells, which suppresses HtrA4-mediated trophoblast invasion by degradation of HtrA4. Conclusion: Physical and functional interaction between trophoblastic HtrA4 and decidual HtrA1 and HtrA3 regulates trophoblast invasion. Significance: This study reveals a novel trophoblast-decidual cell interaction in control of trophoblast invasion.