Lethal necrotizing fasciitis caused by Streptococcus pyogenes is characterized by a paucity of neutrophils at the site of infection. Interleukin (IL)–8, which is important for neutrophil transmigration and activation, can be degraded by S. pyogenes. Blood isolates of S. pyogenes were better able to degrade human IL-8 than throat isolates. Degradation of IL-8 was the result of a single specific cleavage between ⁵⁹glutamine and ⁶⁰arginine within the IL-8 C-terminal α helix. Cleaved IL-8 reduced neutrophil activation and migration. IL-8–cleaving activity was found in partially purified supernatant of a necrotizing fasciitis isolate, and this activity was associated with an ∼150-kDa fraction containing S. pyogenes cell envelope proteinase (SpyCEP). IL-8–cleaving activity corresponded with the presence of SpyCEP in the supernatant. Cleavage of IL-8 by S. pyogenes represents an unprecedented mechanism of immune evasion, effectively preventing IL-8 C-terminus–mediated endothelial translocation and subsequent recruitment of neutrophils