Background: Hepatitis C virus (HCV) infection is estimated to affect over 170 million people worldwide. The current therapy for HCV is pegylated interferon and ribavirin. Anemia is a common side effect of treatment for HCV infection. Recent evidence points to a beneficial role of erythropoietin (EPO) in alleviating INF-ribavirin induced anemia, thereby improving quality of life, enabling higher ribavirin dosage and consequently may improve sustained virological response (SVR). Aim: This study evaluated the incidence of anemia, its relation to serum iron and effect of EPO to maintain ribavirin (RBV) dose and hemoglobin (Hb) level in chronic HCV patients treated with antiviral combination therapy in Zagazig University Hospitals. Patients and methods: 130 patients are included in the study, 100 of them were early responder to treatment and 30 patients were excluded as they were either non responder to treatment or stopped treatment due to other cause including other hematological complications. When (Hb) dropped below 10 gm%, the dose of ribavirin will be reduced 400 mg from baseline dose with follow up weekly for Hb level, if Hb level increased the dose of ribavirin will be returned to full dose, if no improvement and Hb level decreased below 8.5 gm/dl, the patient stopped therapy of INF-ribavirin. Erythropoietin starting with 4000 lU/week subcutaneously if no response within 2 weeks, we increased EPO dose gradually up to12, 000 lU/week. Results: Incidence of anemia was 28%, 28 patients16 males and 12 females. Of our patients 99 patients completed 48 weeks of therapy in the form of either pegylated interferon α2a at a dose of 180 ug/week or α2b at a dose of 1.5 ug/kg body weight plus ribavirin at a dose of 1000-1200 mg/day according to body weight (15mg/kg) and only one patient stopped treatment due to anemia not responding to erythropoietin. Iron, folic acids and multivitamins alone without EPO resulted in significant improvement of anemia in only 13 patients (13/28, 46.4%). EPO was given to 15 patients and good response was obtained in 11 out of 15 patients (73.3 %); so of all 28 anemic patients, 27 completed the course of antiviral therapy. Conclusion: EPO therapy improve compliance to antiviral therapy in chronic HCV patients and may be considered one of standard treatment of anemia resulting from INF-ribavirin therapy as iron, folic acids and multivitamins alone not enough for treatment of anemia in those patients, but further larger studies with longer follow up are required to evaluate the impact on SVR and final outcome in those patients.