The observation of lymphocyte adhesion/homing molecules with ligands (integrins and vascular addressins) on endothelial cells (EC) within target organs during a number of nonlymphoid chronic inflammatory conditions is occurring with increasing frequency. On the basis of evidence from the literature and pilot data on the localization of the putative vascular addressin for humans, HECA-452, in central nervous system (CNS) tissue, it is suggested that molecular recognition on CNS EC might play a pathogenetic role during immune-mediated demyelination in multiple sclerosis (MS). In one of six cases of MS, a case displaying a particularly malignant course, HECA-452 was specifically and reproducibly demonstrated on postcapillary venules in periplaque white matter beyond the zone of active inflammation. In the same case, CD8+ T cells predominated over CD4+ cells. In no case studied were EC positive for HLA-DR (Ia), in contrast to previous reports. Perivascular Ia positivity was common and was always associated with foamy macrophages or pericytes. In view of the occurrence of semiorganized lymphoid collections in a number of chronic inflammatory conditions, several of which are associated with expression of HEV markers, and in MS, it is concluded that examination of molecular recognition events on lymphocytes and EC within the CNS in MS is an area worthy of further study and an area with considerable therapeutic import.