Loss, reduction, or enhancement of the ability to respond to bacterial lipopolysaccharide (LPS) has no influence on survival of mice in a model of postoperative polymicrobial septic peritonitis induced by cecal ligation and puncture (CLP). This was demonstrated by using either mice with a defective Tlr4 gene, which encodes the critical receptor molecule for LPS responses, or mice deficient for LPS binding protein (LBP) or mice sensitized to LPS byPropionibacterium acnes. Though interleukin-12 (IL-12) and gamma interferon (IFN-γ) play an important role in the sensitivity to LPS as well as in the resistance to several infections, loss of these cytokine pathways does not affect survival after CLP. Thus, neutralization of neither endogenous IL-12 nor IFN-γ altered mortality. In addition, IFN-γ receptor-deficient mice demonstrated the same sensitivity to CLP as mice with a functional IFN-γ receptor. However, administration of IFN-γ at the time of operation or pretreatment of both IFN-γ-sensitive and IFN-γ-resistant mice with IL-12 significantly enhanced mortality. This indicates that in the present infection model activation of innate defense mechanisms is not dependent on LPS recognition and does not require endogenous IL-12 or IFN-γ function. Indeed, exogenous application of these two mediators had deleterious effects.