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Despite the public health threat that Staphylococcus aureus (SA) poses, there is no available vaccine. Clinical trials testing vaccine candidates targeting SA surface antigens have had to be ended prematurely due to higher rates of detrimental effects in vaccinated groups when compared to placebo groups. Poststudy analyses of both preclinical and clinical data show that high levels of IFN�� and low levels of IL-17a may be the main drivers of detrimental effects following surface antigen immunization. Here we show that in a mouse bacteremia model, detrimental effects following whole cell vaccination can be lessened depending on the adjuvant used with immunization. We also show that when immunizing with inert mutants of SA superantigens and pore-forming toxins, using certain adjuvants results in a decrease of disease severity by means of producing a stronger antibody response against superantigens as well as greater production of regulatory cytokines (IL-10, TNF��) known to be effective in combating SA.