Dendritic cells (DCs) have been increasingly implicated in the pathogenesis of neuroinflammation, and there is evidence that they are recruited to the brain across the blood-brain barrier. The molecular mechanisms mediating DC trafficking to the central nervous system are poorly understood. This study used an in vitro model of the human blood-brain barrier and monocyte-derived DCs to investigate the role of endothelial cell (EC) adhesion molecules and their ligands in the adhesion of immature and mature DCs to cerebral microvascular ECs. Adhesion of DCs to resting brain ECs was minimal, but activation of ECs with tumor necrosis factor significantly upregulated adhesion. Immature DCs adhered to activated ECs more avidly than mature DCs; this correlated with differences in the expression of adhesion molecule ligands between the mature and immature DCs. Blocking studies indicated that adhesion to cytokine-activated blood-brain barrier endothelium is mediated by intercellular adhesion molecule (ICAM)-1, ICAM-2, platelet-EC adhesion molecule (PECAM)-1, vascular cell adhesion molecule 1, CD18, and DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) for immature DCs and ICAM-1, CD18, DC-SIGN, and PECAM-1 for mature DCs. These results suggest that DC adhesion to cerebral ECs depends on the maturation state of DCs and the activation state of the endothelium, and that it is regulated by specific receptor-ligand interactions. This study thus further highlights the active role of human brain microvascular ECs in neuroinflammation.