Homeobox gene transcription factors play a critical role in normal placental development and are expressed in specialized trophoblast cells. Abnormal trophoblast function is associated with clinically significant pregnancy disorders, including fetal growth restriction (FGR). Our previous studies demonstrated that homeobox gene HLX is expressed in proliferating and migrating (but not invading) human trophoblast cells and that HLX expression is significantly decreased in human FGR. We have also shown that HLX is a regulator of colony-stimulating-factor-1-dependent trophoblast proliferation. Hepatocyte growth factor (HGF) activates trophoblast cell migration in a paracrine fashion, and its receptor, c-met, is expressed on trophoblast cells. Given that HGF is a regulator of trophoblast migration, we hypothesize that HLX is a mediator of HGF/c-met-dependent trophoblast migration but not invasion. Here we investigated the potential role of HLX in HGF/c-met-mediated trophoblast migration and invasion in two human trophoblast-derived cell lines, SGHPL-4 and HTR-8/SVneo. Results showed that in cultured trophoblast cells, HGF stimulation significantly increased HLX mRNA and protein expression. HLX inactivation significantly decreased trophoblast migration but not invasion.