To clarify the mechanism underlying abnormal vasopressin (AVP) secretion in glucocorticoid deficiency, we examined the response of AVP secretion to osmotic stimulus produced by 5% saline infusion and analyzed the possible causative factors in seven patients with hypoosmolal hyponatremia resulting from adrenal insufficiency. In all patients, urinary sodium excretion persisted with urine osmolality exceeding plasma osmolality, and plasma AVP levels relative to plasma osmolality were elevated. Blood urea nitrogen, plasma creatinine, and PRA ranged from low to normal. All patients had nausea or vomiting, three had hypotension, and two had hypoglycemia; however, the primary cause of increased AVP secretion was attributed to none of these stimuli. After 5% saline infusion, patterns of changes in plasma AVP levels in individual patients were variable: levels decreased with increasing plasma osmolality in two patients and remained unchanged in the other five patients. Despite hyponatremia and absence of hypovolemia, thirst was present in the five patients, who responded normally to questions. This abnormality in AVP secretion and thirst was corrected after glucocorticoid replacement with normalization of plasma sodium concentrations and osmolality. Thus, glucocorticoid deficiency in man results in a clinical picture almost indistinguishable from that of the syndrome of inappropriate secretion of antidiuretic hormone. Persistent AVP secretion in this pathological state is due to a loss of hypotonic suppression of the osmostat for AVP release, which may be occasioned primarily by glucocorticoid deficiency per se and aggravated secondarily by multiple nonosmotic stimuli including nausea, hypotension, and hypoglycemia.