Background: Malnutrition is an important prognostic factor potentially influencing clinical outcome of patients suffering from chronic liver disease (cirrhosis; CLD). Malnutrition exacerbates severe muscle loss and hepatic encephalopathy (HE) in cirrhotic patients. New management strategies focussing on improving nutritional status and attenuating CLD-related complications are an unmet clinical need. Aims: We hypothesize supplementation with branched-chain amino acid leucine (LEU) and exercise training (EX) could possibly attenuate muscle mass loss and prevent HE (characterized by brain edema as well as cognitive and psychomotor impairments) in CLD. Methods: CLD was induced in rats following 6-week bile-duct ligation (BDL). Five experimental groups were tested; 1) BDL; 2) BDL + LEU; 3) BDL + EX; 4) BDL + LEU + EX; 5) Sham-operated rats. One week following BDL, rats were submitted to 15 min EX (10 cm/s) every other day and BDL rats receiving LEU, were gavaged daily (1.35 mg/kg) for five weeks. Body weight, muscle (gastrocnemius) mass, metabolic state (calculation of energy expenditure independent of food intake and fecal mass), cerebral edema (specific gravity method) and cognitive/psychomotor function (open-field test; anxiety-like behavior assessment and novel object recognition test; memory testing) were measured in all groups. Results: BDL rats gained less body weight compared to sham-operated rats (125.0±24.9 g vs 226.0±38.5 g; P<0.05). LEU-treated BDL rats display an improvement in brain edema (78.50±0.03% vs 80.27±0.14%; P<0.05), muscle mass (5.48±0.90 g/kg vs 4.83±0.11 g/kg; P<0.05) and circumference (15.6±0.8 cm/kg vs 13.1±0.7 cm/kg ; P<0.05) and metabolic activity (27.48±1.15 vs 32.99±2.35; P<0.05), which was further ameliorated with EX, compared to BDL animals. In addition, BDL rats receiving LEU and EX exhibited less anxiety-like behavior (4.9±1.2 s vs 2.2±0.9 s passed in the center; P<0.01) as well as better novel object recognition memory (69.6±15.2% vs 25.4±9.6%; P<0.01), in comparison with BDL rats. Conclusions: Our results demonstrate that supplemental LEU along with EX reduces body weight and muscle mass loss, improves metabolic activity, attenuates brain edema and improve cognitive and psychomotor function. These findings suggest that strategies aiming at improving nutritional status will attenuate muscle mass loss, reduce the risk of developing HE and therefore improve quality of life and decrease mortality in CLD. LEU supplementation and EX could rapidly be translated into clinical practice. Funding Agency: CIHR.