Serum levels of circulating ICAM-1 are increased in various disorders including inflammatory diseases of the central nervous system (CNS). We recently described an association between high sICAM-1 levels in the serum of patients with multiple sclerosis and disease activity. The functional consequences of increased circulating adhesion molecules are not fully understood. This may simply arise as a consequence of inflammation or may have immune modulating properties. ICAM-1 plays an important role in the recruitment of activated lymphocytes to sites of inflammation within the CNS. We therefore tested the ability of soluble forms of ICAM-1 to prevent adhesion of activated lymphocytes to cerebral endothelial cells. Mitogen-activated blood mononuclear cells (PBMC) as well as PBMCs from patients with active multiple sclerosis adhered to cerebral endothelial cell cultures in vitro. This adhesion could be blocked if lymphocytes were preincubated with a recombinant form of soluble ICAM-1. In addition, serum from patients with active multiple sclerosis and high sICAM-1 levels blocked adhesion in a dose-dependent manner which was abrogated by pre-adsorption to an anti ICAM-1 antibody. Since soluble forms of ICAM-1 are able to block lymphocyte adhesion to cerebral endothelial cells, they may provide new therapeutic tools to interfere with the pathogenesis of inflammatory diseases of the CNS.