In establishing an infection, Streptococcus pyogenes has the capacity to bind to the host extracellular matrix protein fibronectin via its protein F adhesin. Previous studies have suggested that the expression of protein F is stimulated during aerobic growth or upon addition of superoxide-generating agents to the culture under O2-limited conditions. To further explore the role of superoxide, we have examined the transcription of the gene which encodes protein F (prtF) as well as the expression of superoxide dismutase (SOD) under conditions which promote or repress protein F expression. These studies show that prtF transcription is regulated in response to superoxide concentration and that SOD is regulated in different environments in a manner which directly parallels the expression of protein F. A mutant deficient in SOD activity was constructed by insertional mutation into the gene which encodes SOD (sod). The resulting mutant was sensitive to superoxide and aerobic conditions, showed hypersensitive induction of prtF in response to superoxide, and expressed prtF under normally unfavorable O2-limited conditions. These findings suggest that a streptococcal signal transduction system which senses superoxide may coordinately control expression of prtF and sod.