BACKGROUND Severe pericentral zone (zone 3)-based liver injury (LI) may become intractable, with allograft dysfunction after liver transplantation. The phosphodiesterase-3 inhibitor, milrinone, has been reported to attenuate hepatic ischemia-reperfusion injury (IRI). This study clarified how hepatic IRI involved zone 3-based LI, in which zone milrinone was effective, and whether milrinone could improve small intestinal injury (SII) with hepatic IRI. MATERIAL AND METHODS Rats were divided into sham, ischemia-reperfusion (IR), or IR+milrinone groups (n=13 per group). Milrinone was administered intraportally via intrasplenic injection, and whole hepatic ischemia was induced for 30 min. Five hours after reperfusion, serum chemistry and histopathological findings were compared. Expression of CD34 for the detection of altered sinusoidal endothelium as sinusoidal capillarization and cleaved caspase-3 as an apoptosis marker were analyzed via immunohistochemistry. Survival rates were examined after 45 min of whole hepatic ischemia. RESULTS Serum aspartate aminotransferase and direct bilirubin levels were significantly decreased in the IR+milrinone group compared with those of the IR group. The degree of LI, sinusoidal capillarization and apoptosis at zone 3 in the IR group was significantly increased compared with those at the periportal zone (zone 1). These findings at zone 3 in the IR group were improved in the IR+milrinone group. SII with villus congestion and apoptosis in the IR group was significantly attenuated in the IR+milrinone group. The 7-day survival rate was significantly elevated in the IR+milrinone group as compared with that of the IR group. CONCLUSIONS A hepatic IRI model caused zone 3-based LI and SII, which were attenuated by intraportal administration of milrinone.