Anemia of chronic renal failure is associated with a reduced affinity of hemoglobin for oxygen (Hb-O<sub>2</sub> affinity). It has been reported that the correction of renal anemia by recombinant human erythropoietin (rhuEPO) treatment could be associated paradoxically with a further decrease in Hb-O<sub>2</sub> affinity. We investigated changes in the compensatory mechanisms of chronic renal anemia during 25 weeks of rhuEPO treatment, in 19 chronic hemodialyzed (HD) patients. There was no significant variation of mean standard P<sub>50</sub> (P<sub>50</sub>std). Average 2,3-diphos-phoglycerate (DPG) increased after 13 weeks and remained stable. The large interindividual variations prompted us to study ΔP<sub>50</sub>std and ΔHb. We demonstrated a negative correlation between ΔP<sub>50</sub>std and ΔHb. Thus, P<sub>50</sub>std increased in patients who did not immediately correct their anemia and decreased in patients whose Hb values rose. These data showed that the major factor influencing variations of Hb-O<sub>2</sub> affinity in chronic HD patients treated by rhuEPO is the variation of Hb concentrations. In our study, it was demonstrated that the most important rise in P<sub>50</sub>std and 2,3-DPG occurred in patients who were late responders to rhuEPO.