Background: Liver failure/disease leads to hyperammonemia, a central component in the pathogenesis of hepatic encephalopathy. However, it is believed systemic oxidative/nitrosative stress may exacerbate the neuropsychological effects of hyperammonemia observed in patients with liver disease. The present study aims to investigate the role of oxidative/nitrosative stress in 2 rat models of liver disease/hepatic encephalopathy; 1) portacaval anastomosis (PCA), and 2) bile-duct ligation (BDL). Methods: Rats were sacrificed 4 weeks following PCA and 6 weeks following BDL. Arterial plasma and cerebrospinal fluid (CSF) were collected to measure ammonia, reactive oxygen species (ROS), hydrogen peroxide (H2O2) and nitric oxide (NO). S-nitrosylation of cystein thiols was measured in the frontal cortex and plasma proteins by immunoblotting. Brain water content was measured in the frontal cortex using a specific gravimetric technique. Results: Hyperammonemia developed in both PCA (PCA: 181.0 ± 8.5uM vs sham: 60.5 ± 7.0uM; p< 0.0001) and BDL (BDL: 101.1 ± 11.0uM vs sham: 41.7 ± 9.2uM; p< 0.05) rats with PCA rats being significantly higher compared to BDL rats (p< 0.001). Consequently, ammonia increased in CSF in both PCA (PCA: 159.5 ± 15.8uM vs sham: 32.5 ± 3.7uM; p< 0.0001) and BDL (BDL: 123.5 ± 21.7uM vs sham: 23.3 ± 6.1uM; p< 0.05), but no significant change was observed between PCA and BDL. Only rats with BDL demonstrated an increase in plasma levels of ROS (5.8-fold increase vs sham; p< 0.001), H2O2 (3.2-fold increase vs sham; p< 0.05) and NO (2.9-fold increase vs sham; p< 0.05). This was accompanied by an increase in S-nitrosylation of plasma proteins. An increase in brain water content was observed in rats with BDL (BDL: 81.91 ± 0.19% vs sham: 81.23 ± 0.20, p< 0.05) whereas no significant change in brain water content was found in PCA vs sham-operated control rats. Conclusion: Hyperammonemia together with systemic oxidative stress are associated with brain edema in rats with BDL which is not demonstrated in PCA rats where only hyperammonemia is observed. Our findings suggest systemic oxidative stress is implicated in the pathogenesis of brain edema and its synergistic effect with ammonia may lead to progression of hepatic encephalopathy.