Interaction between adhesion molecules on blood-brain barrier endothelial cells (BBB-ECs) and their cognate ligand on lymphocytes promotes transmigration to the CNS. Our data demonstrate that Melanoma Cell Adhesion Molecule (MCAM/CD146) is expressed by a subset of effector memory CD4+ T lymphocytes, co-expressing CD95, CD147, CD11a, CD49d and CCR6. In vitro polyclonal activation induced MCAM expression on as much as 60% of CD4+CD45RO+ lymphocytes. MCAM+ lymphocytes also expressed more RORγ and IL-17 than MCAMneg cells, but comparable levels of IFNγ, IL-2 and GM-CSF both ex vivo and after polyclonal activation. The proportion of MCAM+ lymphocytes was found to be higher in the blood of MS patients than in healthy controls, and was enriched in the CSF of MS patients. When compared to MCAM+ cells obtained from healthy control donors, MCAM+ lymphocytes from MS patients consistently produced more IL-17, in percentage and intensity. During IL-23-driven in vitro polarization of lymphocytes, functional inactivation of MCAM significantly reduced both lymphocyte proliferation and IL-17 production. We further found that MCAM is expressed on the surface of human BBB-ECs in vitro and in situ in MS lesions and that MCAM blockers decreased the recruitment of MCAM+ lymphocytes across BBB-ECs. Our data indicate that MCAM is expressed by both BBB-ECs and a subset of IL-17-expressing effector memory CD4 lymphocytes and that MCAM engagement promotes both IL-17 expression in lymphocytes, as well as the recruitment of these cells across BBB-ECs.