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Background and Objectives Hepatitis C virus (HCV) chronic hepatitis predisposes to iron overload, which negatively influences the prognosis of this infection. Since the underlying mechanisms of this iron overload are undefined, we analyzed the prevalence of altered iron parameters, and the relative contribution of viral, metabolic, and genetic factors in Italian patients.Design and Methods We studied the metabolic and biochemical characteristics of 143 previously untreated, biopsied patients with HCV who were not alcohol abusers. Hepatic iron was determined according to Deugnier, HFE genotype by restriction analysis, hepcidin, hemojuvelin, ferroportin-1, and transferrin receptor-2 mutations by denaturing high performance liquid chromatography and sequencing.Results Increased transferrin saturation was observed in 20%, hyperferritinemia in 22%, and histological iron deposition in 32% of patients. Ferritin was independently correlated with iron stores and host metabolic parameters, whereas hepatic iron deposition was correlated with ferritin and histological severity of hepatitis. Sinusoidal iron deposition was associated with metabolic alterations, including body mass index, insulin resistance, and LDL cholesterol. Conversely, the prevalence of HFE mutations and serum ferritin values increased with the severity of steatosis. The prevalence of HFE and β-globin mutations was not different from that of controls (31% and 2%, respectively). No tranferrin receptor-2, hemojuvelin, or ferroportin-1 mutations were detected, but two patients carried the −72C>T hepcidin promoter mutation. The C282Y HFE mutation, hepcidin and β-globin mutations influenced iron stores. Both carriers of the −72C>T Hepcidin mutation had β-thalassemia trait, moderate iron overload, and liver cirrhosis.Interpretation and Conclusions Iron genes influence iron overload and steatosis development, but the major burden is related to HCV itself and host metabolic factors.