Vasopressin, also called anti-diuretic hormone, is made by the hypothalamus and released by the pituitary gland into the bloodstream. There it travels to the kidney where it reduces the release of water into the urine. With less vasopressin production, the body fails to conserve water, and the result is a trend toward higher plasma sodium concentrations. Hypernatremia may occur in diabetes insipidus, a disease that causes excessive urine production. (It is not the same disease as diabetes mellitus, a disease resulting from impaired insulin production.) The defect involves either the failure of the hypothalamus to make vasopressin or the failure of the kidney to respond to vasopressin. In either case, the kidney is able to conserve and regulate the body's sodium levels, but is unable to conserve and retain the body's water. Hypernatremia does not occur in diabetes insipidus if the patient is able to drink enough water to keep up with urinary loss, which may be as high as 10 liters per day.

Hypernatremia may occur in unconscious (or comatose) patients due to the inability to drink water. Water is continually lost by evaporation from the lungs and in the urine. If the patient is not given water via infusion, the sodium concentration in the blood may increase and hypernatremia could develop. Hypernatremia can also occur in rare diseases in which the thirst impulse is impaired.

Hypernatremia can also occur accidentally in the hospital when patients are infused with solutions containing sodium, such as sodium bicarbonate for the treatment of acidosis (acidic blood). It can also be accidentally induced with sodium chloride infusions, especially in elderly patients with impaired kidney function.

Hypernatremia can cause neurological damage due to shrinkage of brain cells. Neurological symptoms include confusion, coma, paralysis of the lung muscles, and death. The severity of the symptoms is related to how rapidly the hypernatremia developed. Hypernatremia that comes on rapidly does not allow the cells of the brain time to adapt to their new high-sodium environment. Hypernatremia is especially dangerous for children and the elderly.