To study the role of interferon-γ (IFN-γ) in gram-negative shock, mortality was compared in mice receiving either a monoclonal antibody to IFN-γ (H22) or an irrelevant monoclonal antibody (L2-3D9) before or after an LD90 dose of Escherichia coli 0111:B4. H22 given either 1 h before or 0.5 h after bacterial challenge protected mice from death (mortality at 48 h, 28% vs, 83%, P < .001). Serum tumor necrosis factor-α (TNFα) levels and bacterial counts in blood and organs (liver, spleen, heart, and brain) were similar in H22-treated animals and controls. The peak serum TNFa levelswere 95.7 ± 16.4 ngjmL and 80.7 ± 14.9 ngjmL in the H22 and control groups, respectively.These results indicate that IFN-γ plays a significant role in the pathogenesis of gram-negative sepsis.