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Hemochromatosis is a genetic disorder characterized by progressive iron overload which leads to early abnormalities of iron parameters (increased transferrin saturation =TS and serum ferritin=SF) and late clinical complications. The disease is prevalently due to C282Y and H63D mutations in the HFE gene, but additional molecular defects are present in a minority of patients.From January to December 2002 we screened first time blood donors of Piedmont, a region of North-western Italy, for TS45%. Individuals with TS45% underwent a second fasting check, SF assessment and molecular tests, investigating 12 hemochromatosis-associated molecular defects.A total of 13,998 subjects were screened; 868 (6.2%) had TS45% and were recalled. Four hundred and eight-six underwent molecular testing. In this selected population allele frequencies of C282Y, H63D and S65C were 6.8%, 22.4% and 1.0%, respectively. No rare mutations were detected, except E168Q in HFE. When measured during fasting, TS was significantly higher in C282Y homozygotes and H63D/C282Y heterozygotes (p0.05) than in wild type subjects, but not in H63D homozygotes. Hyperferritinemia was documented in 32 cases, 9 with wild type genotype. Mean age, body mass index (BMI) and alcohol intake were higher in this group than in individuals with normal SF.This study is an example of a large, two-step hemochromatosis screening with moderate effort and low cost, that enriches basal C282Y allele frequency by about three-fold. Screening based on genotyping only subjects found to have a TS45% is feasible but, in order to be cost effective should be based on the identification of the two prevalent mutations even in an area where several forms of hemochromatosis have been reported.