Ischemia/reperfusion induced injury is one of the major preoperative complications in liver surgery, so that this work provides evidence that HO-1 gene over expression, and type 5 PDE inhibitions perform a protective role against injury and there is a correlation between both pathways. It has been reported that systems, NO producing nitric oxide synthase (NOS) as well as CO releasing heme oxygenase (HO), are capable of modulating each others activity and demonstrate beneficial effects on the cellular level in a model of hepatocyte cell death in mice. Aim of work : Is to investigate the role of two pathways , HO-1 activattion by use of Cobalt (III) protoporphyrin IX chloride (CoPP) and phosphodi -esterase type 5 inhibition by use of sildenafil,on ischemia reperfusion (I/R) injury of rat liver. To achieve this, fifty male adult white albino rats of average weight between 160 to 200 grams were used The rats were randomly divided into five main groups in which each group included 10 rats : Group I (control group): The rats of this group were subjected to laparotomy and liver exposure was performed with no other further surgical manipulations. Group Π: This group underwent induction of hepatic ischemia reperfusion injury as 45 min of ischemia and 2 hours of reperfusion without injection of drugs. Group III: Rats in this group were subjected to the same procedures as group Π, but they were previously injected (I.P) with CoPP 24 hours before operation at a dose of 5 mg/kg body weight. Group IV: This group underwent the same procedure as group Π but Sildenafil citrate {inhibitor of phosphodiesterase type 5 (PDE-5)} administered intravenously at a dose of 10μg/kgbody weight, 15 min after stabilization of surgery. Group V : In this group, the two pathways were examined by injection of Cobalt (III) CoPP I.P and sildenafil citrate dissolved in saline and administered intravenously. At the end of the experimental period, blood samples were collected to measure serum ALT.The animals were sacrificed and their livers were excised to assess the level of NO and HO-1 gene expression in liver tissues. Samples were fixed in alcohol-formalin-acetic acid, embedded in paraffin and stained with standard haematoxylin-eosin stain for histological evaluation. Stained sections were examined at ×200 and× 400 magnifications for severity of hepatic injury to measure the necrotic index. Results of the present study showed that the serum ALT level and necrotic index were significantly increased in group II(I/R) compared to group I (control) denoting the presence of liver injury with I/R. The serum ALT level and necrotic index were significantly decreased in groups III (I/R +CoPP) and Group IV (I/R+ sildenafil) compared to group II (I/R) denoting a protective from liver injury. In Group V: (I/R+CoPP+ sildenafil), there was marked decrease in the serum ALT level and necrotic index compared to group II (I/R), and no significant change compared to the control)