Regulation of posterior pituitary secretion of vasopressin (AVP) and oxytocin (OT) was studied in rats given electrolytic lesions of ventral nucleus medianus (vNM). As described previously, rats with such lesions were chronically hypernatremic and showed impaired drinking responses to an osmotic challenge. AVP secretion in response to osmotic stimuli also was significantly blunted, although sufficient increases in plasma AVP levels did occur, in association with an abnormally high range of plasma sodium concentrations, to allow urinary concentration comparable to control animals. These findings suggest that vNM lesions cause an upward resetting of the osmotic threshold for AVP secretion. In contrast, hypovolemia, produced by subcutaneous polyethylene glycol treatment, and hypotension, produced by phentolamine treatment, both evoked AVP responses in rats with vNM lesions that were equivalent to those seen in control animals. Plasma OT responses to osmotic and hemodynamic stimuli were analogous to the AVP responses. These findings reproduce the major clinical features observed in humans with the disorder of essential hypernatremia and by doing so support proposals that this disorder is caused by lesions in the vicinity of the anterior hypothalamus that result in selective destruction of afferent osmosensitive inputs to the neurohypophysis.