There is increasing evidence for a relationship between bacterial infections and several cardiovascular disorders. Although the precise mechanism(s) underlying this association is unknown, the direct activation of platelets by bacteria is one possibility. Individual strains of S. sanguis activate platelets in a non-uniform, donor-dependent manner. In the current study, platelet aggregation profiles were obtained for fourteen donors in response to four strains of S. sanguis (2017-78, 133-79, SK112, SK108a) and one of S. gordonii (SK8) . The platelets from all donors responded to strains 2017-78 and 133-79, whereas strains SK112, SK8 and SK108a caused aggregation in one, five and twelve donors, respectively. Immunoglobulin G (IgG) binding to strains 2017-78, 133-79 and SK108a were significantly greater than to strains SK112 and SK8. Absorption of IgG by strain 2017-78 caused significant decreases in IgG binding, and platelet aggregation in response, to all strains. Single-strand conformational polymorphisms were observed in the Fcgamma RIIA gene from four donors. Sequencing revealed two known and two novel point mutations, none of which correlated with the aggregation profile. Thus, platelet activation to the various strains depends on a common IgG and, while in most cases the level of IgG binding to S. sanguis determines platelet responsiveness, neither the levels of IgG nor FcgammaRIIA polymorphisms can fully account for donor variability.