Liver dysfunction including liver cirrhosis and hepatocellular carcinoma (HCC) often causes osmolyte and water imbalance such as edema and ascites. However, the feature and mechanism of liver injury-mediated body fluid dysregulation remain to be elucidated. In the present study, we examined the effect of HCC on body sodium and water balance in rats. Male Wistar rats were administered diethylnitrosamine, a carcinogenic drug, for 8 weeks to establish HCC. Three weeks after the cessation of diethylnitrosamine administration, we evaluated body mass, sodium, and water balance. Compared with control rats, HCC rats reduced body mass and the amount of total body sodium and water. HCC rats also showed enhanced glucocorticoid receptor activity in skeletal muscle, a marker of catabolism. On the other hand, relative tissue sodium and water content per skin and muscle tissue weight were significantly increased in HCC rats. These HCC-induced changes in sodium and water balance were significantly associated with increased 24 hours urinary aldosterone excretion and increased urea osmolyte-driven renal water conservation. These findings suggest that HCC induces osmolyte and water retention at the tissue level in parallel with body mass loss and that enhanced glucocorticoids, aldosterone, and the urea-driven renal water conservation system lead to these HCC-induced changes. The tissue sodium and water retention accompanied by body mass loss may be a causative factor for osmolyte and water imbalance in liver failure.