Extracts containing renal erythropoietic factor (REF) and others which contain renin reportedly enhance erythropoietin (Ep) titers in the plasma of hypoxic nephrectomized rats. Studies reported here were designed to elucidate the mechanism by which renin increases Ep production in the anephric rat. Injection of a renal extract containing renin significantly raised the blood pressure of anephric rats, and when it was injected just prior to exposure to hypoxia and 15 hour postnephrectomy, the resultant plasma Ep level exceeded that observed in rats exposed to the same hypoxic conditions immediately postnephrectomy. In contrast rats made hypoxic 15 hours after nephrectomy, but not given renin, had plasma Ep levels which were lower than those of anephric rats made hypoxic immediately postoperatively. When renin was injected immediately after nephrectomy or into normal rats, it failed to stimulate Ep production. When diazoxide was injected with the renin extract into hypoxic nephrectomized rats, the vasopressor effect of renin was abolished for 4 hours, and the plasma Ep levels were significantly lower than those of hypoxic nephrectomized animals injected only with renin, Injection of angiotensin II into anephric, hypoxic rats had an effect comparable to that of renin on extrarenal Ep roduction. REF was not detectable in the renin preparation. These results are best explained by the concept that renin and angiotensin increase extrarenal Ep production by causing vasoconstriction and consequently hypoxia in extrarenal sites of Ep production. Also of interest is the finding that plasma EP levels of rats, injected with renin and made hypoxic 15 hours postnephrectomy, are higher than those previously reported to occur in anephric rats.