1. Increasing renal perfusion pressure, using an extracorporeal circuit in rabbits and dogs, causes release from the kidney of a vasodepressor substance. 2. The hypotensive response occurs in denervated kidneys, and it is not due to platelet activating factor, nitric oxide, prostanoids or suppression of renin release. 3. In the rabbit, the pressure threshold for release of the hypotensive substance appears to be slightly above normal resting pressures. 4. The source of the hypotensive substance is medullary, since the hypotensive response to increased renal perfusion pressure is abolished in dogs and rabbits whose medullae are damaged by bromoethylamine treatment. 5. The chemical nature of the hypotensive substance remains unknown. 6. Thus the renal medulla appears to possess a hypotensive hormone, released in response to elevation of renal perfusion pressure. Many aspects of the physiology and pathology of the substance and its significance in blood pressure regulation remain to be determined.