Gut mucosal injury observed during ischemia-reperfusion is believed to trigger systemic inflammatory response leading to multiple organ failure. It should be interesting to demonstrate this relationship between gut and multiple organ failure in sepsis model. Intestinal preconditioning can be used as a tool to assess the effect of intestinal ischemia in inflammatory response after LPS challenge. The aim of this study was to investigate the protective effect of intestinal preconditioning (PC) against LPS-induced systemic inflammatory and intestinal heme-oxygenase-1 (HO-1) expression. Endotoxic shock was performed with LPS (10mg/kg IV) with or without intestinal preconditioning which was done before LPS. Rats were first subjected to sham surgery or intestinal preconditioning (PC) with 4 cycles of 1 min ischemia and 4 min of reperfusion 24 hours prior LPS challenge or saline administration. PC reduced significantly fluid requirements, lung edema, intestinal lactate production and intestinal injury. Inflammatory mRNA expressions for intestine and lung ICAM and TNF were significantly reduced after PC and these effects were significantly abolished by Zn-PP, specific HO-1 activity inhibitor, and mimicked by Bilirubin administration. Intestinal PC increased selectively HO-1mRNA expression in intestine, we have observed no expression in lungs. These findings demonstrate that intestinal injury is a important event for inflammatory response and multiple organ injury after LPS challenge. Intestinal HO-1 expression attenuates LPS-induced multiple organ failure by modulating intestine injury and its consequences on inflammatory response. Identification of the exact mechanisms responsible for intestine HO-1 induction may lead to the development of new pharmacological interventions.