Lactulose is used in the treatment of portal-systemic encephalopathy. Although it is usually safe, a case of hypernatremia has been reported. To evaluate further the association of lactulose therapy and hypernatremia, records of patients with hepatic failure treated with lactulose for encephalopathy were analyzed. In 20 of 75 courses of lactulose treatment, serum sodium level exceeded 145 mEq/L. Mortality was 41% in patients in whom hypernatremia developed as compared with 14% in those who remained normonatremic. In persons who died, hypernatremia persisted; in patients who eventually recovered, the serum sodium level returned to normal. The precise mechanism of hypernatremia in these cases is not clearly defined. As an osmotic cathartic, however, lactulose may cause fecal water loss in excess of sodium, resulting in contraction of extracellular fluid volume and, therefore, hypernatremia.