Evidence is presented for an extra-adrenal factor which is necessary for aldosterone or DCA to produce chronic renal Na retention. To study this factor, the left kidney was transplanted to the neck, both adrenal glands and the right kidney were removed and the thoracic inferior vena cava was constricted in six dogs. For a period of two to three weeks, injection of 25 mg/day of DCA resulted in marked Na retention by the transplanted kidney and ascites formed. Neither renal venous hypertension nor the renal nerves were essential for renal Na retention under these circumstances since the transplanted kidney was denervated and its venous drainage was into the external jugular vein with a normal venous pressure. Removal of the caval ligature in four of the dogs was followed by a diuresis and loss of ascites in spite of continued injection of 25 mg/day of DCA. Similar changes occurred during the injection of aldosterone instead of DCA. Measurements of renal hemodynamic function, first, during Na retention and ascites formation and, later, after removal of the caval ligature showed levels of GFR and RPF during Na retention as high as or higher than those observed during the diuresis and subsequent Na balance. In three hypophysectomized dogs with a very low GFR and RPF, Na retention failed to occur during injection of 25 mg/day of DCA. Also, in three adrenalectomized dogs, administration of a large dose of DCA failed to produce chronic Na retention. Finally, four dogs with a large aortic-caval fistula were given 25 mg/day of DCA; sustained Na retention occurred in all four animals and ascites developed in two of the four dogs. A low rate of Na excretion in these animals was present despite a large postprandial rise in GFR. Available evidence indicates that the extra-adrenal factor is either 1) a humoral agent, or 2) some as yet undefined renal functional change.