Background Therapeutic hypercapnia (TH) has been demonstrated to protect several organs ischemia-reperfusion injury.The study aimed to investigate the effects of therapeutic hypercapnia on hepatic ischemia-reperfusion injury (HIRI).Methods Thirty adult male Wistar rats weighing (250 ± 20) g were randomized into 3 groups (n=10 in each), group C (control group), group A (hypercapnia group) and group B (CO2 preconditioning group).A segmental ischemia of the liver was induced by interrupting the blood vessels including the bile duct to the median and left lateral lobes for 60 minutes and all the animals were sacrificed after 240 minutes observation period of reperfusion.Mean arterial pressure (MAP)and the blood gases were measured before ischemia (baseline) and at 30, 60, 120, 180 and 240 minutes after reperfusion.Arterial blood samples were obtained for determination of serum levels of TNF-α, IL-10, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT).The histopathology of liver tissues was evaluated by light microscopy.The NF-κB expression and apoptotic hepatocytes were respectively determined by immunohistochemistry and TUNEL assay.Results The serum levels of liver enzymes and TNF-α were significantly decreased while the IL-10 level was significantly increased in groups A and B than in group C (P ＜0.05), and group B surpassed group A (P ＜0.05).The histopathological scores, the NF-κB immunohistochemical score (IHS) and apoptotic index were significantly lower in groups A and B than in group C (P ＜0.05), and the decrease in group B was more obvious than in group A (P＜0.05).Conclusion Therapeutic hypercapnia attenuates ischemia-reperfusion injury to the liver.Moreover, the effects of CO2preconditioning are outstandingly notable.