Background: Acute-on-chronic liver failure (ACLF) is defined as an acute decompensation of chronic liver disease. Brain edema is frequently observed in hepatic encephalopathy associated with both acute and chronic liver disease. While in acute liver failure, toxic levels of ammonia induce cerebral oxidative stress and brain edema, in chronic liver disease, systemic (not central) oxidative stress and hyperammonemia synergistically cause brain edema. This study investigated the role of both systemic and central oxidative stress and ammonia in relation to brain edema in a rat model of ACLF. Methods: ACLF was induced in male Sprague-Dawley rats by portacaval shunt (PCA), followed 4 weeks later by hepatic artery ligation (HAL). Acute liver failure (ALF) induced by concomitant PCA and HAL, PCA (4 weeks) and SHAM-operated rats were used as controls. ACLF rats were divided into 2 groups that were sacrificed at: 1) coma stage of hepatic encephalopathy (defined as loss of corneal reflex) (ACLF-C) and 2) in parallel with ALF-induced coma (ACLF-P) rats. Brain edema (specific gravimetric technique), ammonia levels (commercial kit) and oxidative stress markers (plasmatic and cerebral reactive oxygen species, fluorescence spectroscopy) were evaluated along with hepatic function (routine biochemistry, haematoxylin-phloxine-saffron histopathology). Results: Coma was delayed by 8h in ACLF compared to ALF rats (p< 0.01). Liver biochemistry markers did not differ between ACLF-C, ACLF-P and ALF rats; liver histopathology showed mild necrosis in ACLF-P, moderate in ALF and severe in ACLF-C. Brain water content was significantly attenuated in both ACLF-C and ACLF-P vs. ALF rats (p< 0.01). Arterial ammonia concentration followed a similar pattern: they were attenuated in ACLF-C: 0.35±0.07 mM and ACLF-P: 0.49±0.14 mM vs. ALF: 1.34±0.09 mM (p< 0.001), but remained high compared to SHAM: 0.06±0.01 mM (p< 0.001). Systemic oxidative stress was present in both ACLF and ALF rats, while cerebral oxidative stress was present only in ALF rats. Conclusion: Brain edema, ammonia levels and oxidative stress are reduced in ACLF rats compared to ALF rats. These findings suggest that during chronic liver failure, compensatory mechanisms that prevent the apparition of brain edema and attenuate oxidative stress during an acute deterioration are developed.