Summary Twelve psychotic reactions are reported in 11 patients with various somatic illnesses treated with ACTH and/or cortisone. Two major patterns occurred: (a) A primarily affective disorder, either manic or depressive; and, more frequently, (b) an organic reaction (toxic psychosis) with associated paranoid-hallucinatory and/or affective (usually depressive) components. No consistent correlation could be obtained with regard to drug dosage and onset, duration, or type of psychosis. Suicidal tendencies were present in several cases. After the ACTH or cortisone was discontinued, termination of the psychosis occurred spontaneously in the organic reactions. The affective disorders required electroconvulsive therapy. A comparison is made between these states and psychoses appearing in naturally occurring hyperadrenalism or Cushing's syndrome. The following factors involved in the production of these psychotic reactions are considered significant: The physiological effects of the hyperadrenal state on the central nervous system. The influence of the underlying disease process. The premorbid personality. Only in a few cases were recognizable psychotic trends present before treatment. It is felt that in most instances the previous personality pattern determined the psychological content of the psychosis, but not its onset. A complete understanding of the interrelationships of all of these physiological and psychological mechanisms is not possible at the present time.