Liver sinusoidal endothelial cell impairment and/or microcirculatory disturbances are thought to induce storage‐related graft failure; however, the respective roles of changes induced by extended cold preservation and transplantation, as well as their interactions, are still unknown. To this end, the alterations of the liver microcirculation and of hepatocyte and sinusoidal endothelial cell functions induced by extended cold preservation and/or transplantation were assessed using an isolated perfused rat liver model combined to an orthotopic rat liver transplantation model. Liver microcirculation remained minimally altered following extended cold ischemia alone, despite a marked deterioration of sinusoidal endothelial cell function, while liver microcirculation alterations were mainly characterized by areas of no‐reflow following transplantation alone. It was only when both procedures were associated that hepatocyte function became markedly compromised, without further deterioration in liver microcirculation. It is concluded that extended cold preservation and transplantation as such are not associated with lethal liver injury. However, the sinusoidal cell impairment and the liver microcirculatory disturbances, induced by both conditions combined, are important factors leading to secondary hepatic nonfunction, which might be triggered by extrahepatic events.