Vitronectin (Vn) is a multifunctional plasma and extracellular matrix glycoprotein involved in cell attachment, coagulation, phagocytosis, and the protection of bystander cells from complement- and T cell-mediated lysis. To determine where Vn is localized and where cells expressing integrin Vn receptors may recognize it in central nervous system (CNS) lesions of multiple sclerosis (MS), CNS tissue samples were immunostained for Vn and the alphav, beta 1, and beta 3 integrin Vn receptor subunits. By light and electron microscopy, Vn was localized within dystrophic, demyelinated axons in active but not chronic lesions, normal or other neurologic disease controls. This localization is distinct from that of other plasma proteins in MS lesions and it differs from the pattern of neuron cell body localization found in other conditions. Microvascular Vn was increased and small numbers of reactive astrocytes were also Vn-positive in active plaques. Endothelial cell expression of the alpha v subunit was increased over controls and that of the beta 1 subunit was decreased whereas both the alpha v and beta 1 subunits were prominently expressed on macrophages and glia in active lesions. The beta 3 integrin subunit was expressed on platelets within and around vessels and was more prominent on endothelial cells in active plaques. The precise functions of Vn in situ are not presently known. These results indicate, however, that the regulation of expression of integrin Vn receptors is complex and that Vn may be recognized and have multiple functions in different microanatomic sites as MS lesions evolve. Intravascular Vn could participate in clotting, thereby contributing to leukocyte extravasation.(ABSTRACT TRUNCATED AT 250 WORDS)