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rHuEPO was administered to eight patients with chronic renal failure (CRF) and uremia (U) for 1 year. Creatinine Clearance (GFR) averaged 14.3 (9-25) ml/min at an Hct of 28% (26-30). Baseline RBC survival by 51Cr T1/2 was highly correlated with GFR (r = 0.66), p less than 0.05 (2), average 21.6 days. Repeat 51Cr T1/2 at 3 months with GFR 10 ml/min at Hct 38% was prolonged by 7 days to 28.6 (p less than 0.005), and at 1 year remained increased to 28 days (p less than 0.001) with Hct 39%, despite further decreased GFR to less than 4 ml/min and need for dialysis. Reticulocytes varied from 1.6% to 7.4 (3-6 weeks) to 3.1 (3 months) and 1.5% (1 year). Bone marrow cellularity increased from 36% to 47% (3 months) and 44% (1 year). M:E ratio decreased from 3.9:1 to 1.7:1 (3 months) to 1.6:1 (1 year). Marrow iron decreased from 4.1/6 to 2.4/6 (3 months) to 1.8/6 (1 year). Doses of rHuEPO had to be reduced to avoid polycythemia. rHuEPO stimulates erythropoiesis in pts with progressive CRF and U for 1 year. The initial increase in hematocrit is due to the early peak of reticulocytes. At 3 months, rHuEPO maintains the increased hematocrit by three mechanisms: 1) increased reticulocytosis, 2) a trend to increased bone marrow erythroid cellularity, and 3) lengthened RBC survival. At 1 year of rHuEPO therapy, the trend to increased marrow cellularity persists, however, the maintenance of target hematocrit is via a lengthened RBC survival. Despite progression of CRF and U, rHuEPO produced RBCs with longer survival than expected. RBC membranes may have been stabilized by rHuEPO.