Bacteria rarely live in isolation and instead engage in interactions with neighboring microbes that alter the fitness of both the individual and the community. These interactions are of clinical relevance because they can result in enhanced colonization and persistence of bacteria at the infection site, a phenomenon known as polymicrobial synergy. An environment where synergy has been especially noted is the oral cavity, where a diversity of microbes coexist in surface-attached biofilm communities. We have been investigating interactions between the Gram-negative periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa) and the Gram-positive oral commensal Streptococcus gordonii (Sg). These organisms display enhanced survival in an in vivo infection model due to defined metabolic interactions involving Aa cross-feeding on the Sg metabolite L-lactate. However, Sg and other streptococci also produce copious amounts of hydrogen peroxide (H2O2), an antimicrobial. Although Aa benefits in co-culture due to the presence of Sg-produced lactate, it is not fully understood how this interaction can proceed in the presence of Sg-produced H2O2. Here we demonstrate that Aa possesses two complementary responses to H2O2: a detoxification or “fight” response mediated by catalase (KatA) and a dispersion or “flight” response mediated by Dispersin B (DspB), an enzyme that dissolves Aa biofilms. Using a murine abscess infection model, we show that both of these responses are required for Sg to promote Aa virulence. While the role of KatA is to detoxify H2O2 during co-infection, 3D spatial analysis of mixed infections revealed that DspB is required for Aa to spatially organize itself at an optimal distance (>4 µm) from Sg, which we propose allows cross-feeding yet reduces exposure to inhibitory levels of H2O2. These results reveal that an antimicrobial produced by a human commensal bacterium enhances the virulence of a pathogenic bacterium by modulating its spatial location in the infection site.