It was posited that the initial host response to Staphylococcus aureus is a contributing factor in the pathogenesis of acute pneumonia. Having previously observed that T cells play a negative role in the pathogenesis of acute pneumonia to S. aureus the contribution of the CD80/CD86 pathway in pathogenesis was investigated. Mice lacking CD80 and CD86 had significantly improved survival in a mouse model of acute S. aureus pneumonia. This was accompanied by significant reductions in several proinflammatory cytokines, including TNF, MIP-2, IL-1β, IL-17 and IL-6, as well as increased numbers of viable alveolar macrophages. Early during infection reductions in cytokine production were evident and cytokine production in response to S. aureus in bone marrow derived macrophages showed decreases in TNF, KC, IL-1α and GM-CSF. Our data suggest that CD80/CD86 signaling plays a significant role in the initial inflammatory response to S. aureus in the airway and could be a potential acute target to reduce the initial inflammatory insult.