The European Best Practice Guidelines for the management of anemia in patients with chronic renal failure recommend the percentage of hypochromic red blood cells (%HRCs) as the best measure of iron use by erythropoietic tissues. They suggest that "sufficient iron should be administered to attain: serum ferritin 100 ng/mL, HRCs <10%. In practice, to achieve these minimum criteria will mean aiming for optimal levels of serum ferritin 200-500 ng/mL, HRCs <2.5%." We increased prospectively the delivered dose of iron supplements to a large (n = 228) unselected hemodialysis cohort with a sustained (24-month) hemoglobin (Hb) outcome meeting the UK Renal Association minimum standard of 85%, greater than or equal to 10.0 g/dL. This was managed through a computer-aided decision support system for erythropoietin (EPO) and intravenous iron sucrose therapy. Hb outcome was maintained with medians between 11.3 and 11.8 g/dL. Median red blood cell hypochromia (%HRCs) decreased from 8% (interquartile range [IQR], 3 to 15) to 4% (IQR, 2 to 8; P < 0.001, U-Mann Whitney test). Serum ferritin level increased from a median of 188 (IQR, 115 to 256) to 480 ng/mL (IQR, 397 to 595; P < 0.001, U-Mann Whitney test). Median EPO dose decreased from 136 (IQR, 83 to 216) to 72 IU/kg/wk (IQR, 33 to 134), which strongly correlated with median %HRCs through the range less than 10% (Spearman's correlation, 0.73; P < 0.01). These data suggest that EPO responsiveness continues to improve toward the normal range for %HRCs (<2.5%) and aspiring to values much less than 10% is cost-effective. The ferritin outcome required to achieve these lower values for %HRC outcome is greater than the current recommended range, although in steady state, the mean iron treatment dose is similar to that in previous studies (ie, approximately 60 mg/wk).