The aim of this study was to investigate whether hyponatremia is a risk factor of overt hepatic encephalopathy (HE) in cirrhosis.A total of 61 patients with cirrhosis were evaluated prospectively for 1 year and all episodes of overt HE were recorded. Predictive factors of HE were analyzed using a conditional model (Prentice, Williams, and Peterson) for recurrent events to assess the relationship between HE and time-dependent covariates. The effects of hyponatremia on the brain concentration of organic osmolytes were analyzed in 25 patients using 1 H-magnetic resonance spectroscopy.Twenty-eight of the 61 patients developed 57 episodes of overt HE during follow-up. Among a number of clinical and laboratory variables analyzed, the only independent predictive factors of overt HE were hyponatremia (serum sodium < 130 mEq / l), history of overt HE, serum bilirubin,and serum creatinine. Hyponatremia was associated with low brain concentration of organic osmolytes, particularly myo-inositol (MI). Furthermore, patients with low brain MI levels had a higher probability of development of overt HE compared with that of patients with high brain MI levels.In patients with cirrhosis, the existence of hyponatremia is a major risk factor of the development of overt HE. Treatment of hyponatremia may be a novel therapeutic approach to preventing HE in cirrhosis.