Hemochromatosis is an autosomal recessive disease of iron metabolism, characterized by progressive iron loading in parenchymal cells of the major organs of the body. This iron overload may result in cirrhosis, diabetes, cardiac failure and arrythmia, hypogonadism, arthritis, hepatocellular carcinoma, and reduced life expectancy. These major complications, which usually develop after the third or fourth decade of life, are often fatal. However, prevention by phlebotomy leads to normal life expectancy if iron excess is detected at a very early stage. Hemochromatosis gene (HFE) has been localized 4.5 Mb telomeric to the HLA-A locus. This gene encodes a 343 AA protein homologous to major histocompatibility class I molecules. Two missense mutations, C282Y and H63D, have been identified in patients. In view of its high frequency in normal subjects (15% -20%), the involvement of the H63D mutation in the pathogenesis of the disease remains controversial and is generally considered as a minor mutation. The C282Y is tightly linked to the disease, as it accounts for 80 to 100% of GH chromosomes in Northern Europe. As the C282Y mutation is observed with lower frequency in Southern Italy and Southern France, the existence of other mutations or other genetic factors could be evoked. Gene HFE encodes a protein bearing homology to major histocompatibility class I molecules. In cellular models, this protein is expressed at the cell membrane in association with โค2 microglobulin. Mutation C282Y, as it substitutes a conserved cysteine for a tyrosine, disrupts the association with โค2m and thus impairs the transfer to the cell surface. Recently HFE has been shown to interact with the transferrin receptor and to decrease the affinity of its ligand. Even if the biologic role of HFE in iron metabolism is unclear, diagnosis and genetic counseling of hemochromatosis were enhanced by the availability of a convenient genotypic test. J. Trace Elem. Exp. Med. 12:361-365, 1999.