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Introduction: By perfusing a liver with oxygenated blood, medications and nutrients at 37C, normothermic machine perfusion (NMP) may improve outcomes after liver transplantation when compared with conventional static cold storage (SCS). Herein is reported the first randomised controlled trial (RCT) comparing continuous NMP with SCS in human liver transplantation. Additional work exploring the mechanisms behind the effects of NMP is also described. Methods: This multinational RCT was initiated by the Consortium for Organ Preservation in Europe (COPE) and involved seven European transplant centres. Adult DBD and type III DCD livers were randomly assigned (1:1) to continuous NMP or SCS. The primary end point was the difference in peak-AST, requiring 220 transplants (90% power). Secondary endpoints included: organ utilisation, preservation time, early allograft dysfunction (EAD), six month graft and patient survival and ischaemic cholangiopathy on MRCP. During NMP, perfusate and bile samples were collected and subsequently analysed to provide information regarding bile salt utilisation and identify markers that may indicate organ quality. Results: 272 livers (135 SCS, 137 NMP) were enrolled, consisting of 194 DBD and 78 DCD organs. 48 livers were discarded (32 SCS [15 DBD, 17 DCD] vs 16 NMP [10 DBD, 6 DCD]; p=0.01). NMP livers experienced significantly longer preservation times than SCS (7hr 21min vs 11hr 39min; p< 0.01). Despite this, better early graft function was observed in the NMP group with regards to peak AST (974 IU/L SCS vs 485IU/L NMP; p< 0.001) and EAD (29.9% SCS vs 12.6% NMP; p=0.002) with the magnitude of these effects being greater for DCD organs (p=0.02). No measurable difference was found in radiological rates of ischaemic cholangiopathy with no demonstrable correlation between MRCP findings and clinically relevant strictures. NMP livers were found to utilise bovine bile salts effectively with bile production and several other biochemical parameters found to correlate with graft quality. Discussion: NMP livers show better early graft function than SCS in terms of peak-AST and EAD, both of which are surrogates for long-term graft outcomes. This is despite better organ utilisation and longer preservation times in the NMP group. NMP can be used to predict organ quality although it is not possible to draw conclusions about markers that may predict viability. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality. The fact that the study has definitively met its primary endpoint should now enable the exploration of the technology's wider potential.