Background: During erythropoietin therapy, scant information exists regarding the optimal target percent saturation of transferrin (TSAT), ferritin and the mode and amount of iron supplementation in pre-dialysis patients with anemia due to chronic kidney disease (CKD). Hypothesis: Pre-dialysis CKD patients may have different needs for iron supplementation than end-stage renal disease subjects during erythropoietin therapy. Methods: Retrospective analysis of pre-dialysis CKD subjects (n = 31) treated with erythropoietin at our institution. Results: In this population our results showed that target hematocrit (33–36%) was achievable with erythropoietin (mean subcutaneous dose 86 ± 17 [SD] units/kg/week) without parenteral iron therapy. The hematocrit increased from a mean baseline value of 28.4 ± 2.7 to 33.6 ± 3.4% at time 1 (4–9 weeks, p < 0.0001), and to 37.7 ± 4.5% at time 2 (10–20 weeks, p < 0.0001). The hemoglobin concentration increased from 9 ± 0.9 g/dl at baseline to 10.7 ± 1.1 g/dl at time 1 (p < 0.0001) and to 12 ± 1.5 g/dl at time 2 (p < 0.0001). Subgroup analyses of patients prescribed <200 mg oral elemental iron per day (n = 10), those with TSAT <20% and/or ferritin <100 ng/ml (n = 19), and those prescribed erythropoietin <80 units/kg/week (n = 12), all showed a significant increase in hematocrit and hemoglobin. Conclusions: Our data show that pre-dialysis CKD subjects respond adequately to erythropoietin at or lower than recommended erythropoietin doses without parenteral iron. This response extends even to subgroups with TSAT and/or ferritin levels deemed to indicate iron deficiency in CKD subjects, and may be due to lack of existence of functional iron deficiency in this group of patients.