Abstract The aim of this study was to determine whether interleukin-10 would alter locally derived and systemic proinflammatory cytokine expression and protect from the lethality of cecal ligation and puncture. Three groups of Sprague-Dawley rats were used. Group 1 underwent cecal manipulation. Groups 2 and 3 underwent cecal ligation and puncture. Group 2 received intraperitoneal saline injections beginning 1 hour after cecal ligation and puncture and every 3 hours thereafter for 24 hours. Group 3 received intraperitoneal interleukin-10 one hour after cecal ligation and puncture and every 3 hours thereafter. Animals were killed at 6 and 24 hours after cecal ligation and puncture or sham operation. Serum tumor necrosis factor-alpha (TNF-α) levels were determined by enzyme-linked immunosorbent assay. TNF-α messenger RNA expression was determined by reverse transcriptase—polymerase chain reaction using β-actin as the internal standard. There was a twofold increase ( P <0.001) in TNF-α mRNA in the liver at 6 and 24 hours after cecal ligation and puncture when compared to rats treated with interleukin-10. There was a twofold increase ( P <0.05) in TNF-α mRNA in the lung observed only at 24 hours after cecal ligation and puncture when compared to rats treated with interleukin-10. Serum levels of TNF-α were elevated at 6 hours in control animals, and this effect was abolished by the administration of interleukin-10. There was no difference in mortality rates at 6 hours (0% for all groups); however, at 24 hours 57% (4/7) mortality was observed in group 2 vs. 0% (0/20) in groups 1 and 3. Interleukin-10 given after the onset of cecal ligation and puncture protects against the lethality of intra-abdominal sepsis.