Our previous analysis of major cell surface proteins of Streptococcus mutans isolated from the blood of a patient with bacteremia showed variations of glucan-binding protein C (GbpC) expression. In the present study, we analyzed the contribution of GbpC of S. mutans to bacteremia occurrence. A GbpC-defective mutant strain (C1) was significantly less susceptible to phagocytosis by human polymorphonuclear leukocytes than its parent strain (MT8148) (P < 0.001). When 21 rats were injected with C1 or streptomycin-resistant MT8148R into the jugular vein, strain C1 was recovered from blood in larger numbers and for a longer duration than MT8148R. Further, infection with C1 resulted in significant increases in serum sialic acid (SSA) concentrations, and splenomegaly, as well as body weight reduction. We also evaluated GbpC expression in 20 clinical oral isolates by immunoblotting with anti-GbpC serum, and found that expression intensity was positively correlated to phagocytosis rate (P < 0.05). These results suggest that S. mutans GbpC may be associated with systemic virulence, since a weak expression of GbpC causes the organisms to be refractory to phagocytosis, resulting in a longer survival of the bacterium in the bloodstream.