The role of tumor necrosis factor-α (TNFα) in the lethal consequencesof intravascular lipopolysaccharide (LPS)or Escherichia coli sepsis was compared with that in bacterial peritonitis. Intravenous administration of E. coli LPS or E. coli (live or dead) resulted in large transient increases in serum TNFα levels, peaking at 90 min at 10,000–30,000 units/mI. In contrast, the serum TNFα response following the induction of bacterial peritonitis was substantially less, peaking at 200–500 units/ml. Sterile peritonitis (essentially nonlethal) and bacterial peritonitis (> 60% lethal) elevated TNFα levels to 1000–2000 units/lavage within the peritoneal cavity 2 h after challenge. Passive immunization with neutralizing goat anti-TNFα IgG improved survival from 8% to 75% in rats administered LPS intravenously but was completely ineffective in protecting rats from lethal E. coli peritonitis. Thus significant differences exist in the role TNFα plays in systemic intravascular models of sepsis and bacterial peritonitis.