The omentum is a large mesenchymal fibro-fatty tissue with remarkable healing capability. It is also rich in immune cells, including macrophages and lymphocytes, within particular structures named milky spots. Clinical observations indicate a high incidence of peritonitis after the removal of the omentum suggesting that it may play a role in sepsis. To test this possibility, male CD-1 mice underwent simultaneous omentectomy and cecal ligation and puncture (CLP), omentectomy-sham operation and CLP alone, and mortality was documented within 72 h post the insults. A significant increase in mortality was observed in mice subjected to omentectomy and CLP in comparison with CLP alone. Mortality was correlated with an increase in cytokine gene expression within the lung after omentectomy and CLP as opposed to CLP alone. However, no differences in bacterial load were observed within the peritoneum or blood between groups. To test the long-term effect of omentectomy, mice were subjected to omentum removal or sham operation, allowed to recover from surgery for 14 or 28 days, and then both were subjected to CLP. In these cases, no differences in mortality were observed between the groups suggesting that the lack of omentum triggers a compensatory mechanism. Finally, omentectomy and sham operation altered the composition of peritoneal immune cells with the disappearance of F4/80 macrophages and the appearance of a new population of F4/80 macrophages within 1 or 14 days post-surgery. The F4/80 positive cells reappeared after 28 days following the procedures. All of these observations suggest that the omentum plays an early role in the outcome from sepsis.