Amphiphilic drugs like chlorphentermine induce a generalized lipid storage disease upon chronic application. The adrenal cortex is among the organs most heavily affected. We therefore determined the urinary corticosterone excretion during the treatment of rats with chlorphentermine and the corticosterone content of the adrenals and its blood level at the end of the treatment period. In addition, the responsiveness of adrenal cortex was tested by application of ACTH. During treatment, the corticosterone excretion declined considerably. Both the corticosterone content of the adrenals and the plasma level were found depressed at the end of a treatment period of 8 weeks. The ACTH evoked response was also diminished. The results indicate that the chlorphentermine-induced lipidosis is associated with a reduced corticosterone production of the adrenal cortex of rats. At present it cannot be decided whether the cortical insufficiency is causally related to lipidotic alterations of the cortical cells, or whether it is caused or additionally influenced by alteration at a higher level, e.g. hypothalamic centers or anterior pituitary.