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Staphylococcus aureusis an important human and animal pathogen associated with an array of diseases, including life-threatening necrotizing pneumonia and infective endocarditis. The success of S. aureusas a pathogen has been linked in part to its ability to manipulate the host immune response through the secretion of toxins and immune evasion molecules. The staphylococcal superantigens (SAgs) have been studied for decades, but their role in S. aureuspathogenesis is not well understood, and an appreciation for how SAgs manipulate the host immune response to promote infection may be crucial for the development of novel intervention strategies. Here, we characterized a widely prevalent, previously cryptic, staphylococcal SAg, SElW, that contributes to the severity of S. aureusinfections caused by an important epidemic clone of S. aureusCC398. Our findings add to the understanding of staphylococcal SAg diversity and function and provide new insights into the capacity of S. aureusto cause disease.