Introduction Hospitalisations from acetaminophen poisoning are increasing (1999, n¼39 045; 2010, n¼52 707. UK, NHS admissions). For the most serious cases there are no effective therapies to assist recovery or prolong survival apart from liver transplantation, which remains a limited resource. We report a clinically-relevant, intensively-managed, model of ALF, which mimics the human condition and has a predictable survival time, for testing of new potential therapies. Methods Nine, 30e40 kg, female pigs were anaesthetised and instrumented for continuous monitoring and management of respiratory and cardiovascular systems and acid-base and electrolyte status, using standardised intensive care protocols and intermittent positive pressure ventilation. Intracranial pressure (ICP) was monitored but not treated. Six animals were induced to ALF with acetaminophen administered via an oroduodenal tube: a loading dose of 0.25 g/kg was followed by hourly doses of 0.5e4.0 g adjusted according to serum acetaminophen concentrations. At irreversible ALF (defined as prothrombin time >3 times normal), continuous renal replacement therapy (CRRT) was initiated. Three animals acted as controls with initiation of CRRT at 20 h and termination at 40 h. Results Following onset of acetaminophen dosing, peak serum acetaminophen concentrations of 367630 mg/l were achieved at 12 h and irreversible ALF at 19.361.8 h. Death occurred predictably 12.662.7 h after irreversible ALF. Development of ALF was associated with progressive hypotension (p<0.001) and metabolic acidosis (p¼0.001), not observed in controls. Mean arterial pressure (MAP) was maintained with aggressive fluid therapy, noradrenaline and terlipressin. Metabolic acidosis was corrected successfully with bicarbonate and CRRT. In ALF, there was significant (p<0.001) rise in ICP compared to controls with sudden marked increase prior to death: at study end, ICP in ALF and controls was 41.268.6 mm Hg and 22.762.5 mm Hg respectively. Death was preceded by abrupt increase in central venous pressure, fall in MAP and bradycardia. Histopathology confirmed moderate to marked acute centrilobular to midzonal hepatocyte degeneration and necrosis in ALF. Conclusion A predictable model of ALF, with death due to multiorgan failure, has been successfully validated for translational studies for therapies designed to prolong survival in man.