Septic shock is a major cause of mortality in neonates. The hypothesis was tested that neonatal age is associated with altered sensitivity to shock-inducing bacterial products or proinflammatory cytokines (or both). Mice of different ages were inoculated with various doses of lipopolysaccharide (LPS), superantigenic staphylococcal enterotoxin B (SEB), or recombinant tumor necrosis factor-alpha (rTNF-alpha), alone or in combination with the sensitizing agent D-galactosamine. Neonatal mice were markedly more susceptible to LPS-induced lethality but more resistant to SEB than were adults (P < .05). Mice of different ages did not differ, however, in their sensitivity to lethal activities of rTNF-alpha. Neonatal susceptibility to LPS and SEB correlated directly with plasma TNF-alpha but not IFN-gamma levels, which was confirmed by TNF-alpha and IFN-gamma blockade experiments. These data document marked age-related differences in the pathophysiology of septic shock and suggest that IFN-gamma is not an obligatory mediator of either LPS- or SEB-induced lethality in neonates.