We studied the role of NF-κB in acute inflammation caused by gut ischemia-reperfusion through selective ablation of IκB kinase (IKK)-β, the catalytic subunit of IKK that is essential for NF-κB activation. Ablation of IKK-β in enterocytes prevented the systemic inflammatory response, which culminates in multiple organ dysfunction syndrome (MODS) that is normally triggered by gut ischemia-reperfusion. IKK-β removal from enterocytes, however, also resulted in severe apoptotic damage to the reperfused intestinal mucosa. These results show the dual function of the NF-κB system, which is responsible for both tissue protection and systemic inflammation, and underscore the caution that should be exerted in using NF-κB and IKK inhibitors.