Background: The shortage of organs for transplantation requires acceptance of livers from marginal donors. Hypothermic oxygenated machine perfusion (HOPE) improves mitochondrial function decreasing oxidative injury during reperfusion. Normothermic machine perfusion (NMP) allows viability assessment and extended preservation. We aim to assess whether a combination of both techniques would merge benefits and increase the rescue rate of marginal organs. Methods: Ten discarded human livers were randomly allocated to two experimental groups: (1) NMP group, in which 5 organs were perfused at 37oC using an acellular oxygen carrier based perfusate for 6 hours; (2) HOPE+NMP group, in which 5 organs had 2 hours of HOPE at 10oC followed by 4 hours of NMP. Viability was assessed at the end of 6 hours perfusion using the lactate clearance criteria. Results: The HOPE phase decreased the mitochondria respiratory rate (oxygen uptake, p=0.043; pCO2 in the perfusate, p=0.040) and increased the median ATP content (p=0.016). This resulted in slower oxygen consumption during rewarming and decreased tissue expression of markers of oxidative injury (4-hydroxynonenal, p=0.008) and activation of the inflammatory cascade (Kupffer cells, p=0.016; Vascular Cell Adhesion Protein 1, p=0.050). Livers deemed non-viable at the end of the NMP had lower ATP levels (p=0.050) and higher lactate levels (p=0.020). All HOPE+NMP group livers were deemed viable compared with three (60%) in the NMP alone group (p=0.222). Conclusion: The combined protocol of HOPE+NMP together merged benefits of the techniques and increased the rescue rate of marginal livers into the pool of transplantable organs compared with NMP alone.