ACTH is destroyed in serum primary by several serum-endopeptidases (trypsin, plasmin, thrombin, kallikrein), as is demonstrated by paper chromatographic analysis of the degradation fragments. Secondary the liberated peptides are hydrolyzed by serum-aminopeptidases. The rate of inactivation of ACTH by serum in vitro was studied in various diseases including endocrine disorders with hypercorticalism or diminished adrenal cortical function. The hydrolysis of ACTH by serum is increased only in hepatobiliary diseases. The speed of the degradation of ACTH in serum is small and cannot explain the short disappearance rate of the hormone in blood stream. Infusion of streptokinase increases the plasmin concentration and therefore the inactivation of ACTH in blood. In these circumstances it seems possible to decrease the adrenocorticotrophic effect of ACTH in vivo.