Rationale: Staphylococcus aureus is a major pathogen complicating post-surgical care. Objective: To test the effect of sterile laparotomy (LAP) on pulmonary clearance of S. aureus in a murine model. Methods: Control and LAP mice were infected intranasally with 10⁸CFU of S. aureus. Microbial clearance, pulmonary leukocyte recruitment and cytokine profiles were compared between the groups. Antibody neutralization or cytokine gene knockout mice were used to evaluate the role of cytokines. Measurements and Main Results: Laparotomy resulted in a ten-fold increase in S. aureus lung CFU on days 2 and 3 post infection. Both groups cleared the infection by day 4. No defect in leukocyte recruitment into the lungs was observed in LAP-infected animals; however, an increase in the number of Mac-3 positive cells and a significant decrease of cells with high surface expression of Fc-R suggest suboptimal activation of leukocytes in the lungs of infected LAP animals. Infected LAP mice had decreased expression of interferon (IFN)- and increased expression of mRNA for IL-13 in the lungs on day 1 post-infection and decreased levels of IL-6, KC and MIP-2 in brochoalveolar lavage at day 2 post-infection. Neutralization of IFN- mimicked the effect of LAP with impaired clearance on day 2. Conclusions: Sterile LAP induced temporary deactivation of innate immune responses to pulmonary S. aureus challenge. Impaired microbial clearance was accompanied by altered cytokine expression and suboptimal activation of pulmonary leukocytes. Lack of early IFN- induction in the infected lungs of LAP animals is a likely mechanism contributing to the observed phenotype.