Background and Aims: In chronic liver disease (CLD), the muscle plays a compensatory role in clearing ammonia and therefore muscle mass loss increases the risk of hepatic encephalopathy (HE). It has been demonstrated that systemic oxidative stress is implicated in the pathogenesis of brain edema, however only in male rats with CLD. Therefore, our aim is to identify the impact of sex on the pathogenesis of HE and brain, including ammonia-induced overt HE. Methods: Male and female bile-duct ligated (BDL) rats (and respective Shams) were evaluated for minimal HE and ammonia-precipitated overt HE (lethargy/loss of righting reflex). In addition, liver markers, hyperammonemia, systemic OS, muscle mass and ammonia clearance were evaluated. Results: Female and male BDL rats had similar liver impairment (ALP, AST, and bilirubin (p<0.001)) and HE (motor-coordination and night activity (p<0.05)) vs. respective Shams. Contrary to males, females BDLs did not develop muscle loss (p<0.05), brain edema or severe HE episode (p<0.005). Furthermore, degree of hyperammonemia as well as muscle ammonia clearance were similar between male and female BDLs but systemic OS was significantly lower in females (p<0.01). Discussion: Our findings demonstrate that female BDL rats develop CLD, HE and similar degrees of hyperammonemia compared to male rats. Differently from males, female BDL did not develop muscle mass loss, brain edema nor severe HE following ammonia challenge. The protection against brain edema in female BDLs is primarily due to low systemic OS but whether brain edema or systemic OS renders male BDLs most susceptible to ammonia-precipitated insults remains to be determined.