There has been renewed scientific interest in the role of oral bacteria in systemic disease in recent years. The incidence of infective endocarditis (lE) in the UK has been rising lately. Dental plaque bacteria of the genus Streptococcus are recognised causative agents of lE. Oral Streptococcus gordonii produces several factors that are thought to be involved in promoting lE. One of these, designated surface platelet adherence protein A (PadA), has been only recently identified. This study aimed to determine mechanisms by which PadA functional domains interacted with platelets, and platelet integrin GPIIbIIIa, under static or shear conditions. The role of PadA in platelet interactions in relation to a well-characterised platelet adhesin (Hsa) was clarified. Furthermore, the interactions of PadA protein with extracellular matrix (ECM) components were investigated. This work identified PadA as a protein that binds activated platelets and confers shear resistance. A two-step S. gordonii-platelet adherence model is proposed, whereby Hsamediated platelet activation then enables PadA platelet adhesion and activation. This is the result of, at least in part, the presence of an integrin-like motif NGR within PadA binding to platelets under static conditions. PadA also binds components of the ECM including fibronectin, vitronectin and von Willebrand factor. However, PadA-mediated bacterial cell adherence to vitronectin and activated platelets occurs only in the presence of Hsa. PadA and Hsa together modulate biofilm formation on salivary pellicle, but in this case Hsa only functions in the presence of PadA. Thus it is proposed that PadA and Hsa may form a macromolecular complex on the surface of S. gordonii. PadA-like family proteins appear to be structurally conserved and are found in a range of lE pathogens. Increased knowledge of the molecular interactions occurring between streptococci and platelets will enable translation into new strategies for the prevention or treatment of infection-associated cardiovascular diseases .