Recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) has proven to be an effective agent in treating the anemia of chronic renal failure. Of patients enrolled in recent phase III trials in the United States, 97% have responded with near normalization of hematocrit within 12 weeks of therapy. Small numbers of patients, however, may exhibit sluggish or minimal responsiveness to treatment. In these patients, loss of responsiveness due to red cell substrate depletion (in particular, iron deficiency) or underlying inflammatory disease may occur at any time during the treatment calendar, whether at induction of therapy or during maintenance treatment. Primary unresponsiveness at initiation of treatment may also result from such potentially reversible abnormalities as aluminum intoxication, poorly controlled hyperparathyroidism, and, possibly, severe azotemia. These abnormalities can be investigated in a systemic fashion and frequently corrected so that successful treatment can resume.