Streptococcal peptide of virulence (SpoV) is a Streptococcus pyogenes (group A streptococcus (GAS))-specific peptide that is important for GAS survival in murine blood, and the expression of the virulence factors streptolysin O (slo) and streptolysin S (sagA). We used a spoV mutant in isolate MGAS315 to assess the contribution of the SpoV peptide to virulence by using a murine model of invasive disease and an ex vivo human model (Lancefield assay). We then used antibodies to SpoV in both models to evaluate their ability to decrease morbidity and mortality. Results showed that SpoV is essential for GAS virulence, and targeting the peptide has therapeutic potential.