Erythropoietin (EPO) gene expression is positively regulated by hypoxia-inducible factor-1, which binds to the 3′ enhancer of the EPO gene. EPO expression is negatively regulated by GATA, which binds to the GATA site in the 5′ promoter. Anemia of renal disease is believed to be caused by damage to the EPO-producing cells in the kidney as a result of renal failure. However, even mild renal failure can reduce the serum concentrations of EPO, suggesting that, in addition to the damage to EPO-producing kidney cells, uremic toxin(s) may play an important role in the pathogenesis of the anemia of renal disease. NG-monomethyl-L-arginine (L-NMMA), which competes with L-arginine as a substrate for nitric oxide synthase (NOS), is undetectable in nonuremic subjects, but is markedly elevated in patients with chronic renal failure. We have previously shown in the Hep3B cell line that L-NMMA suppresses EPO expression by upregulating GATA through the suppression of NOS activity, and that inhibition of EPO production with NG -nitro-L-arginine methyl ester (L-NAME) is reversed by pretreatment with L-arginine in mice. In this study, eight patients with anemia of renal disease, who were in the predialysis state of chronic renal failure, were enrolled in a nonrandomized study. All patients were anemic, and had hemoglobin (Hb) levels ranging between 7.9 and 10.8 g/dL. Patients with iron deficiency anemia, hemolytic anemia, and hematological malignancies were excluded. Blood urea nitorgen (BUN) levels were 29.7–90.1 mg/dL, and creatinine (Cre) levels were 1.1–3.8 mg/dL. Eight patients with anemia of renal disease were treated orally with L-arginine at 1.3 g/day for 8 to 22 wks. During this period, patients did not receive blood transfusions, or treatment with iron, vitamins or recombinant human EPO. Six patients responded to the treatment with increased levels of Hb and EPO, and three of these showed improved renal function. The EPO concentrations decreased in two nonresponders. There were no significant adverse effects. These limited data suggest that oral administration of 1.3 g/day of L-arginine can significantly improve EPO production and reverse anemia without adverse effects in patients with anemia of renal disease who are in the predialysis state of chronic renal failure. More studies including younger patients with severe renal dysfunction are in progress.