A 54-year-old woman had seizures and a focal neurologic deficit associated with hyponatremia induced by a thiazide diuretic. Prompt correction of hyponatremia by administration of hypertonic saline solution was followed by resolution of all neurologic defects. Metabolic balance studies and rechallenge with hydrochlorothiazide were undertaken to investigate the mechanism of the thiazide-induced hyponatremia. Abnormal vasopressin secretion was shown by a plasma vasopressin concentration of 0.5 microU/ml with a plasma osmolality of 268 mOsm/kg water after administration of a fluid challenge consisting of 45 ml/kg body weight. Rechallenge with chlorothiazide while on a sodium- and potassium-controlled balanced diet resulted in a decrease in serum sodium concentration (136 to 124 mEq/L) and plasma osmolality (283 to 261 mOsm/kg) within 18 hours. During this period, urine losses of monovalent cation were only 55 mEq and body weight was constant at 48.2 kg. A second challenge while the patient received all fluids and electrolytes intravenously again resulted in decreased serum sodium concentration (134 to 126 mEq/L) after urinary loss of only 69 mEq of cation. Thus this patient's hyponatremia cannot be accounted for solely by changes in external water and electrolyte balance; the rapidity with which changes were produced suggests that osmolar inactivation, probably intracellularly, may contribute to the severe hypotonicity seen in some patients.