Pro-inflammatory cytokine over-expression may be implicated to the pathogenesis of anemia in chronic heart failure (CHF) through the suppression of bone marrow erythropoiesis. Erythropoietin administration has anti-inflammatory and anti-apoptotic properties in experimental CHF models and improves exercise capacity in anemic CHF patients. The present study investigates the effects of recombinant human erythropoietin analogue darbepoetin-alpha on circulating pro-inflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with CHF and anemia. Forty-one CHF patients (NYHA class: II-III; left ventricular (LV) ejection fraction (EF) <40%; hemoglobin <12.5g/dl; serum creatinine <2.5mg/dl) were randomized to receive either 3-month darbepoietin-* at 1.5 microg/kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). LV systolic function, plasma B-type natriuretic peptide (BNP), inflammatory markers (TNF-, IL-6, CRP), anti-inflammatory cytokine IL-10, endothelial adhesion molecules (soluble ICAM-1 and VCAM-1) and soluble apoptosis mediators (soluble Fas, soluble Fas ligand), and 6-min walking distance were assessed at baseline and 3 months post-treatment. In darbepoetin- treated patients, plasma BNP (451 (62-2770) from 802 (476-4440) pg/ml, p=0.002), IL-6 (6.5+/-4.7 from 10.5+/-7.8 pg/ml, p=0.013) and soluble Fas ligand (53.2+/-16.6 from 59.2+/-17.9 pg/ml, p=0.023) decreased significantly, while LVEF (32+/-6 from 26+/-6%, p<0.001), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, p<0.001) and 6-min walked distance (274+/-97 from 201+/-113m, p<0.01) increased significantly. No significant changes were observed in the placebo arm, except for a worsening in 6-min walked distance (p=0.044). In conclusion, darbepoetin-alpha reduces circulating pro-inflammatory cytokine IL-6 and apoptotic mediator soluble Fas ligand in CHF patients with anemia, with a parallel improvement of cardiac performance and exercise capacity.