Careful evaluation of iron status is of pivotal importance in end-stage renal disease patients before and during r-HuEPO therapy. Absolute (ferritin < 100 micrograms/l) and functional (ferritin normal or supranormal, transferrin saturation < 20%, hypochromic red blood cell [RBC] > 5%) iron deficiency are the main reasons for r-HuEPO hyporesponsiveness. Adequate iron supplementation allows significant reduction of r-HuEPO dosage and costs. Oral iron supplementation is recommended for predialysis and peritoneal dialysis patients with serum ferritin > 100 micrograms/l, whereas i.v. iron supplementation is the therapy of choice in hemodialysis patients. However, neutrophil impairment and other possible side-effects (e.g. cardiovascular complications, malignancy) as a result of i.v. iron therapy suggest that overtreatment with i.v. iron should be avoided.