Histone deacetylase inhibitors (HDACIs) have recently emerged as promising anti-cancer drugs to induce cell cycle arrest, cytodifferentiation, and apoptosis. It is suggested, however, that HDACIs promote cell migration and invasion depending on the cell type. We have reported previously that treatment with HDACIs including trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) or progesterone in combination with estrogen can induce cytodifferentiation of endometrial adenocarcinoma Ishikawa cells through up-regulation of glycodelin, a progesterone-induced endometrial glycoprotein. Given the reported role of glycodelin in cell motility and the migration-modulating potential of HDACIs, we here investigated using wound healing assay and trans-well migration assay whether ovarian steroid hormones, TSA, and SAHA affect cell migration in endometrial cancer cell lines, Ishikawa and RL95-2. Treatment with ovarian steroid hormones, TSA, and SAHA enhanced cell migration together with up-regulation of glycodelin. SAHA-augmented cell migration was almost completely blocked by gene silencing of glycodelin. Furthermore, overexpression of gycodelin alone resulted in increased cell motility in Ishikawa cells. Our results collectively indicate that glycodelin positively regulates cell motility acting as a mediator of HDACI-enhanced endometrial cell migration, suggesting the involvement of glycodelin in the dynamic endometrial gland morphogenesis during menstrual cycle. Our results raise a possibility that the use of HDACIs in the therapy for glycodelin-inducible endometrial and presumably other gynecological cancers may enhance invasion in a case that the HDACIs fail to exert differentiation-inducing and/or anti-proliferative effects.