ABSTRACTLarge numbers of bacteria coexist in the oral cavity.Streptococcus sanguinis, one of the major bacteria in dental plaque, produces hydrogen peroxide (H2O2), which interferes with the growth of other bacteria.Streptococcus mutans, a cariogenic bacterium, can coexist withS. sanguinisin dental plaque, but to do so, it needs a means of detoxifying the H2O2produced byS. sanguinis. In this study, we investigated the association of three oxidative stress factors, Dpr, superoxide dismutase (SOD), and AhpCF, with the resistance ofS. sanguinisto H2O2. The knockout ofdprandsodsignificantly increased susceptibility to H2O2, while the knockout ofahpCFhad no apparent effect on susceptibility. In particular,dprinactivation resulted in hypersensitivity to H2O2. Next, we sought to identify the factor(s) involved in the regulation of these oxidative stress genes and found that PerR negatively regulateddprexpression. The knockout ofperRcaused increaseddprexpression levels, resulting in low-level susceptibility to H2O2compared with the wild type. Furthermore, we evaluated the roles ofperR,dpr, andsodwhenS. mutanswas cocultured withS. sanguinis. Culturing of thedprorsodmutant withS. sanguinisshowed a significant decrease in theS. mutanspopulation ratio compared with the wild type, while theperRmutant increased the ratio. Our results suggest thatdprandsodinS. mutansare involved in coexistence withS. sanguinis, and PerR is associated with resistance to H2O2in regulating the expression of Dpr.