Background: Whether erythropoiesis-stimulating agent (ESA) can retard the progression of renal failure remains unclear. To date, this hypothesis has been supported primarily by three small prospective clinical studies. However, in two recent large trials, no renoprotective effect was observed. The present study was designed to evaluate the potential renoprotective effect of ESA. Methods: This was a 6-month, single-center, prospective study. Sixty predialysis anemic patients with chronic kidney disease (CKD) stage 4 to 5 and a hematocrit (Ht)＜30% were randomly assigned to two groups: Group 1, anemic patients treated with, ESA; amid Group Ⅱ, anemic patients not treated with ESA. Another 30 patients with CKD stage 4 to 5 and a Ht≥30%, hot receiving ESA treatment, were also recruited as the control group (Group Ⅲ). ESA therapy with either recombinant human erythropoietin (rHuEpo) or darbepoetin was prescribed in Group Ⅰ, with a target Ht of 30% for 6 months. In all three groups, an oral iron supplement was give, if necessary, with a target serum, ferritin level of approximately 300 ng/l. Results: After 6 months of ESA therapy, anemia was significantly unproved in Group Ⅰ, with a change in mean Ht from 27.0%±2.1% to 29.8%±3.0% (p=0.001). No significant change in Ht was noted in Groups Ⅱ and Ⅲ. Renal function tests including creatinine and estimated glomerular filtration, rate (GFR-MDRD) shooed no significant difference between the three groups. As for individual patient groups, however, the renal deterioration in Group I (from 14.8±5.6 to 13.9±5.1 ml/min l.73 m^2, p=0.149) timid Group Ⅲ (from 18.6±5.6 to 16.8±5.3 ml/min/1.73 m^2, p=0.061) were not significant while a significant deterioration in renal function was noted in Group Ⅱ (from 16.8±5.7 to 13.7±5.2 ml/min/1.73 m^2, p=0.000). Further statistical analysis of all patients was done to compare between patients with and without renal deterioration in 6 months. There was still no significant difference in percentage of ESA therapy between the two groups. Conclusion: In this study, we could hot show a significant retardation of renal deterioration in patients with ESA therapy: however, a beneficial trend seems to be noted. We conclude that renoprotective effect of ESA in CKD stage 4 to 5 patients remains uncertain.