Background: Resuscitation of hemorrhagic shock causes global ischemia-reperfusion (I/R) injury and it contributes subsequent morbidity and mortality. Cellular hypoxia and reoxygenation is a basic component of ischemia-reperfusion (I/R) injury and the generation of reactive oxygen species (ROS) is one of the most important mechanisms in I/R injury. Thus, decreasing or scavenging ROS is an important method for reducing reperfusion injury. In animal models of I/R injury, it has been reported that high-flow reperfusion resulted in severe reperfusion injury and gradual reperfusion decreased injury. In addition, abrupt reoxygenation has been reported to generate ROS much higher in hypoxic endothelial cells. Thus, this study was designed to investigate the effect of slow reoxygenation in stepwise fashion on cellular injury and to examine the effect of blood pressure-targeted stepwise reperfusion mimicking slow reoxygenation on mortality and liver injury in hemorrhagic shock. Methods: Pressure-controlled hemorrhagic shock was induced in male Sprague-Dawley rats for 1 hour and then rats were resuscitated with predetermined blood pressure-targeted stepwise resuscitation (stepwise reperfusion) protocol or rapid normalization of blood pressure (rapid reperfusion). Survival time and hemodynamic changes were recorded and compared. Blood samples and liver tissue were harvested. Using cellular hypoxic injury model in RAW 264.7 cells, the effect of reoxygenation speed was investigated. Abrupt reoxygenation and slow reoxygenation (0.8% increase of oxygen concentration per 15 min) were compared. Results: In animal experiments, stepwise reperfusion significantly decreased mortality and it reduced histological liver injury (all p<0.05). The ROS generation estimated by DCF-DA assay, nitric oxide (NO) production, IL-1βand IL-6 were also significantly lower in the stepwise reperfusion group than in the rapid reperfusion group (all p<0.05). In addition, phosphorylation of Akt, GSK-3βand Bad were significantly increased in the stepwise reperfusion compared with rapid reperfusion and expression of cleaved caspase-3 was significantly lower in the stepwise reperfusion group than in the rapid reperfusion group. (all p<0.05). In vitro experiments using RAW 264.7 cells, slow reoxygenation significantly decreased cell death and LDH release. The ROS generation and NO production, IL-1βand IL-6 were significantly lower in slow reoxygenation compared with abrupt reoxygenation and slow reoxygenation augemented Akt survival pathways (all p<0.05). Conclusion: Blood pressure-targeted stepwise resuscitation in hemorrhagic shock decreased mortality and liver injury and slow reoxygenation decreased cell death and cytotoxicity in RAW 264.7 cells exposed to hypoxia. These effects may be related with decreased ROS production by slow reoxygenation.