Bacterial infections are often polymicrobial.Pseudomonas aeruginosaandStaphylococcus aureuscause chronic co-infections, which are more problematic than mono-species infections. We found that the production ofS. aureusmembrane-bound pigment staphyloxanthin (STX), was induced by theP. aeruginosaexoproduct, 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). The induction phenotype was conserved inP. aeruginosaandS. aureusclinical isolates examined. When subjected to hydrogen peroxide or human neutrophils,P. aeruginosasurvival was significantly higher when mixed with wild-type (WT)S. aureus, compared to a mutant deficient in STX production orP. aeruginosaalone. In a murine wound model, co-infection with WTS. aureus, but not the STX-deficient mutant, enhancedP. aeruginosaburden and disease compared to mono-infection. In conclusion, we discovered a novel role forP. aeruginosaHQNO mediating polymicrobial interactions withS. aureusby inducing STX production, which consequently promotes resistance of both pathogens to innate immune effectors. These results further our understanding of how different bacterial species cooperatively cause co-infections.