Background: European guidelines stress that iron status should be regularly assessed for the optimal management of renal anemia. These guidelines include the hemoglobin content of reticulocytes and the percentage of hypochromic RBC as markers for functional iron deficiency. Recently, equivalents of these indices have become available on the automated hematology analyzer Sysmex XE-2100, these being reticulocyte hemoglobin equivalent (Ret-He) and DF-HYPO XE, respectively. Methods: In a prospective study, we closely monitored these parameters in dialysis-dependent patients with end-stage renal disease during the switch from a first-generation epoetin (EPO) once weekly to a third-generation EPO [continuous erythropoietin receptor activator (CERA)] once monthly. As a control, patients staying on EPO β were monitored. Results: During follow-up, no changes in erythrocyte indices were noticed in the EPO β group. By contrast, in the CERA group, a decrease in Ret-He and an increase in DF-HYPO XE were transiently found 7–10 days after administration. The transient state of functional iron deficiency could not be prevented by extra intravenous iron. Conclusion: Fluctuations in Ret-He and DF-HYPO XE have to be taken into account when these parameters are used for the assessment of iron-deficient states. We suggest that a fixed time point in the CERA schedule should be chosen for iron monitoring.