Interferon-gamma (IFN-γ) has been demonstrated to improve outcome following localized infection and hemorrhagic shock in experimental studies. We sought to determine the effects of IFN-γ in a clinically relevant murine model of intra-abdominal polymicrobial sepsis. Fifty male BDF1 mice, each weighing 23–28 g, underwent cecal ligation and puncture (CLP) followed by administration of subcutaneous injections of IFN-γ 100–22,500 U or vehicle control immediately post-CLP and then daily. In a second set of experiments, 60 mice underwent daily injections of vehicle control or 100 U IFN-γ 24, 48, or 72 hours prior to CLP. Interferon-gamma administered following CLP led to increased mortality and earlier deaths in a dose-dependent fashion (p < 0.05). Interferon-gamma given 24, 48, or 72 hours prior to CLP resulted in no demonstrable benefit when compared with animals that did not receive IFN-γ (p = 0.14, p = 0.94, and p = 0.97, respectively). While IFN-γ has been reported to be of value in selected clinical situations by improving resistance to infection, it may not be capable of conferring protection following surgery or trauma with intra-abdominal sepsis, and in fact may be detrimental.