Treatment of myeloma-associated chronic anemia with recombinant human erythropoietin (rHuEPO) has been shown to be successful in the majority of patients. We have morphometrically investigated bone marrow sections from the iliac crest of 20 anemic myeloma patients prior to rHuEPO therapy. The 15 responding patients were re-examined after three months and, if possible, after 6 and 12 months of treatment. Significant differences were found between responders and nonresponders prior to therapy. Nonresponders presented with a pronounced shift to the right in their erythroid bone marrow cell compartment and partly with higher serum levels of endogenous erythropoietin. During rHuEPO therapy, responders showed increases in all subsets of erythropoiesis and in the total amount of hemopoietic tissue. Response was accompanied by a marked drop of serum ferritin levels, a rise in serum levels of transferrin receptors and the emptying of bone marrow iron stores; the World Health Organization performance status improved. Responders tended to present with less advanced disease stages and better performance status and showed significantly longer survival times. Loss of responsiveness to rHuEPO was observed in one patient during the terminal stage of the disease. In conclusion, morphometric examination of bone marrow biopsies during the course of rHuEPO therapy showed that the response achieved in hemoglobin values was clearly mirrored in equivalent increments of the erythroid bone marrow cell compartment.