Adequate body iron stores are crucial to assuring rapid and complete response to recombinant human erythropoietin (rHuEPO). In the present study, markers of iron storage were examined in 27 patients with normochromic, normocytic anemia undergoing acute rHuEPO (150 to 300 U/kg t.i.w.) treatment for anemia. We calculated projected iron needed for new hemoglobin synthesis from the difference between initial and target hemoglobin concentrations, initial iron reserves available from initial serum ferritin levels, and net projected surplus or deficit from the difference between needs and reserves. Of 22 patients predicted to develop iron deficiency (mean projected deficit 268 +/- 70 mg), 20 developed evidence of exhausted iron stores (transferrin %sat less than 16 or ferritin less than 30 micrograms/liter) before reaching target hemoglobin; two predicted to become deficient (projected deficit less than 100 mg) did not; and all five predicted to avoid iron deficiency (mean projected surplus 177 +/- 20 mg) remained iron replete. During acute rHuEPO therapy net body iron balance remained neutral in patients receiving no iron supplements and increased 5 mg/kg in patients prescribed oral ferrous sulfate. However, in patients given iron dextran i.v. less than 60% of elemental iron administered became measurable as iron stores or usable for hemoglobin synthesis.