Objectives: To determine: a) whether the cell-mediated immune response during sepsis differs in females vs. males; and b) whether the survival rate in females is different than in males after a septic insult. Design: A prospective, randomized animal study. Setting: University research laboratory. Subjects: Male and female proestrus C3H/HeN mice. Interventions: After anesthesia, male and proestrus female mice underwent cecal ligation puncture to induce sepsis. The mice were killed at 24 hrs after the onset of sepsis. Measurements and Main Results: Splenocyte proliferation, as well as splenocyte interleukin (IL)-2 and IL-3 release, was determined by bioassay. In additional studies, survival rate after septic challenge was measured over 10 days. Splenocyte proliferative capacity and splenocyte IL-2 and IL-3 release were markedly decreased in male, but not in female, septic mice. Furthermore, the survival rate of septic female proestrus mice was significantly higher than in comparable male mice. Conclusions: These results support the concept that the immune response of females differs from males, and that females are immunologically better positioned to meet the challenge of sepsis.