We measured serum erythropoietin levels serially in 31 renal-transplant recipients treated with cyclosporine, using the recently developed recombinant human erythropoietin-based radioimmunoassay. The mean (+/- SEM) serum erythropoietin concentration in these patients before transplantation (14 +/- 2 U per liter) was similar to that in normal subjects who did not have anemia. A transient postoperative 9-fold increase (range, 0- to 74-fold) in the serum erythropoietin levels was followed by a smaller (3-fold) and sustained (28 +/- 3 days) second elevation. The initial increase occurred in the absence of graft function and was not accompanied by an erythropoietic response, whereas the second increase was associated with graft recovery and the complete resolution of the anemia. Serum erythropoietin levels returned to normal as the hematocrit rose above 0.32. Thereafter, the hematocrit continued to rise toward normal, while the serum erythropoietin levels remained normal. The patients in whom erythrocytosis or iron-deficiency anemia developed had persistently elevated serum erythropoietin levels. We conclude that in patients who have undergone renal transplantation, slight increases in endogenous erythropoietin levels induce erythropoiesis to the same extent as do large doses of exogenous erythropoietin in patients with uremia. Moreover, once initiated, erythropoiesis in renal-transplant recipients may be sustained by normal serum erythropoietin levels. These results suggest that the restoration of renal function improves the erythropoietic response to erythropoietin.