The iron-regulated surface determinant B (IsdB) protein from Staphylococcus aureus plays a fundamental role as a receptor for the plasma and extracellular matrix protein vitronectin. Vn binding was strictly related to the expression of IsdB by bacterial strains. Adherence to and invasion of epithelial and endothelial cells by S. aureus expressing IsdB was promoted by Vn, which acts as a bridge between IsdB and the Vn host receptors.