Plasma cortisol was analyzed every 20 minutes for 24 hours in six psychotically depressed patients and eight normal persons. The depressives, while ill, secreted substantially more cortisol, had more secretory episodes, and more minutes of active secretion; throughout day and night, cortisol concentration was markedly elevated both at the beginning and end of secretory episodes, and cortisol was actively secreted during late evening and early morning hours when normally secretion is minimal. After treatment, the patients' secretory patterns normalized. Biological half life of cortisol remained normal throughout. The data suggest an abnormal disinhibition during depressive illness of the neuroendocrine centers regulating adrenocorticotrophic hormone release. Such neuroendocrine activation has been produced in animals following depletion of brain biogenic amines; a similar mechanism may be involved in the hypersecretion of cortisol in certain depressed patients.