Tumor necrosis factor (TNF)-α, a cardinal molecule in the cascade of sepsis-induced host injury, binds to two distinct receptors: tumor necrosis factor receptor (TNFR) 1 and TNFR2. We used the cecal ligation and puncture model of polymicrobial sepsis to elucidate the role of these receptors in sepsis pathogenesis. Mice lacking TNFR1 had prolonged survival with less hypothermia, whereas mice lacking TNFR2−/− had shortened survival and more profound hypothermia than wild-type mice. TNFR1−/− and TNFR2−/− mice had increased serum concentrations of interleukin (IL) 1β and total TNF-α (free plus receptor bound) compared with wild-type mice, but there were no differences in IL6 or IL10 concentrations. Furthermore, free TNF-α was markedly elevated in the serum and peritoneal fluid of mice lacking TNFR2, supporting a role for this receptor in regulating the concentration of TNF-α. Lastly, apoptosis of ileal crypt epithelial cells was increased in mice lacking TNFR1, but there were no differences in lymphocyte apoptosis. These data suggest that in sepsis, TNFR1 mediates much of the TNF-α-induced pathology, whereas TNFR2 mediates protective effects.