Hemodialysis (HD) patients with functional iron deficiency (FID) often develop resistance to recombinant human erythropoietin (Epo). The contributory role of chronic inflammation and oxidative stress in its pathogenesis is poorly understood. We assessed the effect of vitamin C, an antioxidant, on Epo-hyporesponsive anemia in hemodialysis patients with un-explained hyperferritinemia levels. Thirty-one of 132 with Hb 15 patients received standard care and 300 mg of intravenous vitamin C with each dialysis session (group 1) and 15 patients received standard care (group 2). After 3 months, Hb and transferrin saturation levels significantly increased in group 1 but not in group 2 (p < 0.05%). Hemoglobin content in reticulocyte and serum ferritin decreased significantly in group 1 but not in control group. In conclusion, hemodialysis patients with refractory anemia and adequate iron stores, vitamin C improved responsiveness to Epo by augmenting iron mobilization and possibly via antioxidant effect.