Neonates have a higher prevalence of bacterial sepsis and have greater morbidity and mortality from sepsis than other infants and children. Our understanding of the inflammatory and immunological responses to sepsis is hampered by the lack of appropriate neonatal murine models. In the present report, we have developed a cecal slurry model of generalized peritonitis in neonatal mice (age range, 5-7 days) and compared the outcome and the innate and adaptive cellular responses of these animals with those of the young adult animals (age range, 7-10 weeks) with sepsis induced either by cecal slurry administration or by cecal ligation and puncture. Neonatal mice were more susceptible to sepsis and mounted a markedly attenuated systemic inflammatory response compared with young adult animals (specifically, decreased plasma interferon γ; interleukins 1α and 1β; regulated on activation, normal T expressed and secreted (RANTES); and tumor necrosis factor α concentrations). Compared with young adult animals, septic neonatal mice did not lose significant percentage or absolute number of splenic CD4+ T cells. These findings suggest that the cecal slurry model of generalized peritonitis can produce sepsis in neonatal mice with dose-dependent lethality. Inherent differences in the host response to polymicrobial sepsis between neonatal and young adult animals may explain the increased sensitivity of the neonatal mouse to generalized peritonitis.