In patients with acute liver failure, the occurrence of hepatic encephalopathy (HE) defines poor prognosis. Ammonia is central in the pathogenesis of HE and its arterial levels predict brainstem herniation which accounts for mortality in about 30% of patients with acute liver failure. A Cochrane-metanalysis concluded the lack of proof for any available therapy for HE and placebo controlled clinical trials in HE are justified. Studies on interorgan metabolism suggest that ammonia levels in liver failure are regulated by the critical interplay of ammonia, glutamate and glutamine metabolism involving the muscle, gut and kidneys. Based on this knowledge, we have formulated a novel concept to reduce plasma ammonia, L-Ornithine Phenylacetate (OP). L-Ornithine stimulates ammonia removal through glutamine synthetase (glutamine production) in skeletal muscle and phenylacetate excretes the ornithine-related glutamine as phenylacetylglutamine in the urine. To evaluate the therapeutic efficacy of OP, groups of pigs with ALF (induced by liver devascularization) were treated with L-ornithine 0.05 g/kg/hr (i.v) and phenylacetate 0.07 g/kg/hr (i.g). Over 8 hours, ICP (expressed as percent baseline) did not rise significantly in the sham group (23.2±14.6%), but increased significantly in the ALF group (102.8±18.4%, p<0.01 compared to sham). In the ALF+OP-treated group, increased ICP was attenuated (46.3±35.7%, p<0.05 compared to ALF). Arterial concentrations of ammonia did not change significantly in the sham group over 8 hours (34.6±3.8 µmol/L), but in the ALF group it increased to 676.3±46.1 µmol/L (p<0.001 compared to sham). This increase was attenuated in the OP-treated group (230.9±67.8 µmol/L, p<0.01 compared to ALF). In conclusion, OP, a novel approach to treating hyperammonemia and HE, successfully attenuated an increase in arterial concentrations of ammonia and ICP in this large-animal model of ALF. As both L-ornithine and phenylacetate are already available for human use, this data showing its usefulness in pigs with ALF could translate quickly into providing the much needed therapy for HE patients.