Immunocompromise after a major injury is presumed to be a predisposing factor for sepsis. Mice subjected to sublethal cecal ligation and puncture (CLP) and challenged 5 days later with Pseudomonas aeruginosa had more bacterial growth in lung tissue, lower serum interferon γ (IFN-γ) and interleukin (IL) 12, and higher serum IL-10 when compared with sham CLP mice challenged with Pseudomonas. To test the functional significance of these alterations in cytokine production in the immune response to bacteria, we administered IFN-γ and anti-IL-10 to post-CLP mice before the Pseudomonas challenge. Administration of IFN-γ and anti-IL-10 did not improve bacterial clearance or mortality in post-CLP mice. In further studies, we administered IFN-γ to IL-10 knockout mice before a challenge with P. aeruginosa. Our results showed no significant differences in bacterial clearance or mortality in IL-10 knockout mice with or without IFN-γ treatment compared with wild-type controls. Finally, because most mortality occurred within 2 to 3 days of the Pseudomonas challenge in the aforementioned studies and was likely associated with a marked proinflammatory response, we investigated the effect of IFN-γ and anti-IL-10 on clearance of Pseudomonas in C3H/HeJ mice, which do not mount an exaggerated proinflammatory response to endotoxin or Gram-negative bacteria. Neither clearance of the Pseudomonas bacteria nor mortality was improved in C3H/HeJ mice receiving anti-IL-10 and IFN-γ. These results suggest that the suppressed IFN-γ and IL-12 responses, in combination with an exaggerated IL-10 response to P. aeruginosa challenge after injury, do not correlate with bacterial clearance or survival.