Interferon-gamma (IFN-gamma) has been implicated in the mortality of animal models of endotoxemia. On the other hand, the specific role of IFN-gamma in the development of organ inflammation in a model of polymicrobial sepsis has not been elucidated. In this study, we hypothesized that IFN-gamma plays an important role in lung inflammation after cecal ligation and puncture (CLP). To verify this hypothesis, lung tissue was removed 5 h after CLP or from sham controls. The mRNA expression (by RT-PCR) of IFN-gamma was increased in lung homogenates of CLP rats compared to sham controls. Using immunohistochemistry, we show for the first time the increased presence of IFN-gamma staining cells in the lung following CLP. Only very small amounts of positive staining for IFN-gamma was observed in lungs of sham controls. The presence of IFN-gamma in the lung 5 h after CLP correlated with a twofold increases in lung superoxide generation and MPO activity (index of neutrophil sequestration). Plasma and lung nitrite levels (breakdown product of nitric oxide) were also significantly increased in CLP rats. IFN-gamma antibody (1.2 mg/kg, i.v.) administered immediately after CLP significantly decreased lung superoxide levels to levels similar to the sham controls without affecting MPO activity, or lung or plasma nitrite levels. These results provide evidence that IFN-gamma may contribute to lung inflammation 5 h following CLP via increased production of superoxide.