Previous study has shown that melanoma cell adhesion molecule (MCAM/CD146) is highly expressed by invasive trophoblasts in normal pregnancy, but it is absent in pregnancy disorder pre-eclampsia in which the invasion ability of trophoblast is seriously impaired. The mechanism that CD146 affects the trophoblast invasion was investigated. Immunofluorescence staining revealed that CD146 was selectively expressed on invasive intermediate trophoblasts, but was not expressed on non-invasive cytotrophoblasts and syncytiotrophoblasts. Functional studies showed that the anti-CD146 antibody significantly inhibited the migration of trophoblasts and the activity of matrix metalloproteinases secreted by trophoblastic cells, which are two critical factors for trophoblast invasion. The results demonstrate that adhesion molecule CD146 plays a critical role in trophoblast invasion, which will provide a valuable molecular model for the study of trophoblast and tumor cell invasion.