To assess the effect of recombinant human erythropoietin (r-HuEPO) treatment on renal function, the slopes of the regression lines of the reciprocal of serum creatinine versus time were compared in 26 patients with renal insufficiency (serum creatinine ranged from 2.3 to 11.7 mg/dl) followed for a period of 2.7 to 24 months. Ten patients received r-HuEPO and the anemia was corrected (Group I). Sixteen patients did not receive r-HuEPO. Ten of them were anemic (Group II) and six had normal hematocrits (Group III). All study groups were matched for age, diagnosis and degree of renal insufficiency. All cohorts were followed prospectively (Period B, from the first day of the study to the time of data analysis or dialysis and transplantation); renal function was also examined retrospectively (Period A, from the first day of the study to the time of first renal function measurement). Hematocrit was lowest in Group II control patients, 27%, highest in the Group III control subjects, 43%, and intermediate in Group I EPO-treated patients, 36%. Serum creatinine uniformly increased in all three groups of patients. The rate of progression, as measured by the slopes of the reciprocal of serum creatinine versus time, however, was similar in all three groups of subjects and during both periods. The mean slopes for Group I patients before and after r-HuEPO were, respectively, -0.0058 and -0.0054, that of the control cohorts with low and normal hematocrit during period B were -0.0063 and -0.0010, respectively. Thus, it appeared that neither r-HuEPO administration nor a normal hematocrit accelerated the deterioration of renal function in these patients with renal insufficiency.