Trophoblast invasion is crucial for embryo implantation and placentation. Excessive trophoblast invasion leads to hydatidiform moles and choriocarcinoma. PPM1A is a phosphatase which dephosphorylates and inactivates a broad range of substrates, including TGF-β, MAP kinases, p38 and JNK kinase cascades, and is involved in tumor suppression. The objective of this study was to investigate the expression of PPM1A in normal and malignant human placenta and its role in trophoblast invasion, which shares many similarities with invasion of tumor cells. By Western blotting and immunocytochemistry, significantly higher expression of PPM1A in human placental villi at term was found as compared with that during the first trimester. Furthermore, the expression level of PPM1A protein in hydatidiform moles was lower compared with that during normal pregnancy. We further investigated the function of PPM1A in extravillous trophoblast cell line HTR8/SVneo. Transwell migration and Matrigel invasion assays demonstrated that PPM1A siRNA significantly promoted the motility and invasiveness of the cells. Gelatin zymography showed that knockdown of PPM1A with siRNA elevated the expression of pro-matrix metalloproteinase pro-(MMP)-9, but down-regulated tissue inhibitors of metalloproteinases (TIMP)-2. The present data indicate that PPM1A plays a critical role in the regulation of normal placentation by inhibiting trophoblast migration and invasion.