Virulence factors regulated by the CovRS/CsrRS two-component gene regulatory system contribute to the invasive diseases caused by group A Streptococcus (GAS). To determine whether the streptococcal secreted esterase (Sse), an antigen that protects against subcutaneous GAS infection, is one of these virulence factors, we investigated the phenotype of a nonpolar sse deletion mutant strain (Δsse). In addition, we examined the effects of covS mutation on sse expression. As assessed using a mouse model of subcutaneous infection, the virulence of the Δsse strain is attenuated and the overall pathology is reduced. Furthermore, GAS was detected in the blood and spleens from mice subcutaneously infected with the parental strain, whereas mice subcutaneously infected with the Δsse strain had no GAS present in their blood and spleens. The ability of the mutant to survive in the subcutis of mice appeared to be compromised. The growth of the Δsse strain in rich and chemically defined media and nonimmune human blood and sera was slower than that of the wild-type strain. Complementation restored the phenotype of the Δsse strain to that of the wild-type strain. The wild-type, Δsse, and complement strains had no detectable SpeB activity. Expression of Sse is negatively controlled by CovRS. These findings suggest that Sse is a CovRS-regulated virulence factor that is important for the virulence of GAS in subcutaneous infection and plays an important role in severe soft tissue infections and systemic dissemination of GAS from the skin.