Chronic hepatitis C is often associated with liver iron overload, which may affect the long-term prognosis and the response to antiviral treatment. The occurrence of hemochromatosis (HFE) mutations were studied to determine whether may contribute to the liver iron overload of chronic hepatitis C patients. The prevalence of two HFE mutations (C282Y and H63D) in 120 chronic hepatitis C patients was determined and the findings were correlated with clinical, histological and virological features. Hepatic iron was determined semiquantitatively by a histochemical hepatic iron index, defined as the ratio of a histochemical staining score to the patient's age, after correction for heterogeneous lobular iron distribution. Serum hepatitis C virus (HCV) RNA was measured by bDNA assay and typed by restriction fragment length polymorphism. Liver HCV RNA was measured by a semiquantitative strand-specific reverse transcription-polymerase chain reaction (RT-PCR). Excess liver iron was stained in the liver of 36 patients (30%). Siderotic patients had the same geographic origin, serum and liver HCV RNA levels and H63D and C282Y mutations frequency as non-siderotic patients. However, siderotic patients were older (P = 0.015), more frequently males (P = 0.02), less frequently infected with HCV genotype 3 (P = 0.037) and had a higher liver fibrosis score (P = 0.008). The liver iron content did not correlate with the serum or liver HCV RNA titers. Ten of the 36 patients with liver siderosis had neither a history of excess alcohol intake, multiple transfusions, or HFE mutations. In conclusion, the pathogenesis of the liver iron overload in chronic hepatitis C patients cannot be fully explained by the occurrence of HFE mutations. The exact mechanism of iron accumula-tion in these patients therefore remains unexplained.