Liver pathology was assessed in 135 patients with well-defined genetic hemochromatosis ranging from mild disease to severe overload. Three lesions were clearly linked to iron-overload intensity--scarce sidero-necrosis, mild inflammation, and progressive fibrosis. Iron-free foci made of typical or dysplastic hepatocytes were found in 7.4% of the cases. An original grading allowed a reliable quantification of iron and the study of cellular and lobular distribution of iron, which permitted (a) the accurate identification of a decreasing iron gradient in hepatocytes from zone 1 to zone 3 in all cases, (b) the definition of a threshold hepatocytic/mesenchymal iron ratio related to the appearance of sidero-necrosis and to the development of fibrosis, and (c) demonstration that non-iron-related factors (mainly alcoholism) could shift iron from hepatocytes to sinusoidal cells without an increase in the total liver iron amount. This study provides a dynamic view of the iron overload process and suggests that sidero-necrosis and progressive sinusoidal iron overload play a role in the development of fibrosis in human genetic hemochromatosis.