1. An attempt was made to evaluate the pathophysiology of symptoms of hyponatremia as related to changes in brain water and electrolytes. Studies were carried out in 66 hyponatremic patients and 5 groups of experimental animals. 2. In hyponatremic patients, symptoms (depression of sensorium, seizures) correlated well with plasma Na+ (r = 0.64, p less than .001), but there was substantial overlap. In patients with acute hyponatremia, all were symptomatic and 50% died. Among patients with hyponatremia of at least 3 days duration, sympatomatic patients had plasma Na+ (115 +/- 1 mEq/L) which was significantly less (p less than .001) than that of asymptomatic patients (plasma Na+ = 122 +/- 1 mEq/L). Among symptomatic patients, mortality was 12% and 8% had seizures, while none of the asymptomatic patients died or had seizures. 3. Among 14 patients with acute (less than 12 hrs) hyponatremia, the mean plasma Na+ was 112 +/- 2 mEq/L. All such patients had some depression of sensorium and four had grand male seizures. Seven of these patients were treated with hypertonic (862 mM) NaCl, while four were treated only with fluid restriction. Of the seven patients treated with hypertonic NaCl, five survived, while three of four patients treated with fluid restriction died. There was no evidence of circulatory congestion or cerebral damage in the patients treated with hypertonic NaCl. 4. Among rabbits with acute (2-3 hours) hyponatremia (plasma Na+ = 119 +/- 1 mEq/L), all had grand mal seizures and 86% died. All such animals had cerebral edema (brain H2O content 17% above control value) but brain content of Na+, K+ and Cl- was normal. 5. Rabbits with 3 1/2 days of hyponatremia (plasma Na+ = 122 +/- 2 mEq/L) appeared to be asymptomatic, even though brain water content was 7% above normal (p less than .01). 6. Rabbits with 16 days of more severe hyponatremia (plasma Na+ = 99 +/- 3 mEq/L) were weak, anorexic, lethargic and unable to walk. Brain water content was 7% above normal, although brain osmolality (218 +/- 12 mOsm/kg H2O) was similar to plasma (215 +/- 8 mOsm/kg). Brain content of Na+, K+, Cl- and osmoles was 17 to 37% less than normal values, so that the brain established osmotic equilibrium with plasma primarily by means of a loss of electrolytes. 7. These studies suggest that in patients with hyponatremia, symptoms and morbidity are only grossly correlated with either magnitude or duration of hyponatremia. Symptoms appear to correlate best with the interplay between a net increase in brain water versus a loss oof brain electrolytes. However, even asymptomatic animals have subclinical brain edema when plasma Na+ is below 125 mEq/L, and such edema may cause permanent brain damage. Thus, many patients with similar levels of plasma Na+, particularly when they are symptomatic, should probably be treated with hypertonic NaCl infusions.