In this study, we hypothesized that Streptococcus suis induces the shedding of adhesion molecules from the surface of human brain microvascular endothelial cells (HBMEC), which may contribute to the ongoing pathophysiological processes of meningitis. When HBMEC were stimulated with whole cells of S. suis S735, significantly larger amounts of soluble intercellular adhesion molecule-1 (sICAM-1) were shed into conditioned medium while basal levels of soluble E-cadherin and P-selectin were unaffected. At a multiplicity of infection of 1 and 10, S. suis increased the concentration of sICAM-1 3.5- and 5-fold, respectively. A capsule-deficient mutant of S. suis induced more shedding than the parental strain. In addition, an S. suis cell wall preparation dose-dependently stimulated ICAM-1 shedding. Specific inhibitors of tyrosine kinase, mitogen-activated extracellular kinase 1, 2, and c-JUN N-terminal kinase significantly reduced S. suis-mediated ICAM-1 release. ICAM-1 shedding was also inhibited by a specific inhibitor of matrix metalloproteinases. The capacity of S. suis to induce ICAM-1 shedding has many functional implications that may contribute to the pathophysiological process of meningitis.