Background A substantial subgroup of asthmatic patients have “nonallergic” or idiopathic asthma, which often takes a severe course and is difficult to treat. The cause might be allergic reactions to the gram-positive pathogen Staphylococcus aureus , a frequent colonizer of the upper airways. However, the driving allergens of S aureus have remained elusive. Objective We sought to search for potentially allergenic S aureus proteins and characterize the immune response directed against them. Methods S aureus extracellular proteins targeted by human serum IgG4 were identified by means of immunoblotting to screen for potential bacterial allergens. Candidate antigens were expressed as recombinant proteins and used to analyze the established cellular and humoral immune responses in healthy adults and asthmatic patients. The ability to induce a type 2 immune response in vivo was tested in a mouse asthma model. Results We identified staphylococcal serine protease–like proteins (Spls) as dominant IgG4 -binding S aureus proteins. SplA through SplF are extracellular proteases of unknown function expressed by S aureus in vivo . Spls elicited IgE antibody responses in most asthmatic patients. In healthy S aureus carriers and noncarriers, peripheral blood T cells elaborated TH 2 cytokines after stimulation with Spls, as is typical for allergens. In contrast, TH 1/TH 17 cytokines, which dominated the response to S aureus α-hemolysin, were of low concentration or absent. In mice inhalation of SplD without adjuvant induced lung inflammation characterized by TH 2 cytokines and eosinophil infiltration. Conclusion We identify Spls as triggering allergens released by S aureus , opening prospects for diagnosis and causal therapy of asthma.