To survive macrophage killing is critical in the pathogenesis of viridians streptococci-induced infective endocarditis (IE). Streptococcus mutans, an opportunistic IE pathogen, generally does not survive well phagocytic killing in murine macrophage RAW 264.7 cells. A putative two-component system (TCS), ScnR/ScnK from S. mutans, was investigated to elucidate the mechanisms underlying bacteria-cellular interaction in this study. Both the wild-type and mutant strains were phagocytosed by RAW 264.7 cells at a comparable rate and an increased intracellular susceptibility during a 5 h incubation period was observed with the scnRK-null mutants. The amount of reactive oxygen species (ROS) in activated macrophages was reduced significantly after ingesting wild-type, but not scnRK-null mutant strains, suggesting that increased macrophage killing of these mutants is due to the impaired ability of S. mutans to counteract ROS. Additionally, both scnR- or scnRK-null mutants were more susceptible to hydrogen peroxide. Interestingly, scnRK expression was unaffected by hydrogen peroxide. These experimental results indicate that scnRK is important in counteracting oxidative stress in S. mutans, and decreased susceptibility to phagocytic killing is at least partly attributable to inhibition of intracellular ROS formation.