Proline-, glutamic acid- and leucine-rich protein-1/modulator of non-genomic activity of estrogen receptor (ER) (PELP1/MNAR) is a novel nuclear receptor (NR) co-activator that plays an essential role in the actions of ER. Emerging findings suggest that PELP1/MNAR is a novel proto-oncogene, whose expression is deregulated in several hormone-responsive cancers, including endometrial cancer. In this study, we demonstrate that PELP1/MNAR is widely expressed in endometrial carcinoma cell lines. To investigate its possible role in endometrial carcinoma progression, we adopted an RNA interference technology to downregulate PELP1/MNAR expression in Ishikawa endometrial carcinoma cells. PELP1/MNAR downregulation substantially reduced cell proliferation, and the cells in which PELP1/MNAR expression was knocked down also exhibited a decreased migration and invasion ability, as shown by Boyden chamber and invasion assays. The results showed that the expression of MMP-2 and MMP-9 was also decreased. These results suggest that PELP1/MNAR plays a role in endometrial cancer progression and metastasis, and that PELP1/MNAR may be a potential therapeutic target for endometrial cancer.