To detemine the impact of HFE genotyping on diagnosis of hemochromatosis and the prevalence of HFE mutations in patients with liver disease, a crosssectional study was carried out in two academic medical centers. 66 patients with hereditary hemochromatosis (HH) and 132 patients with other liver diseases (OLD) were evaluated, comparing routine hematology and chemistry tests, serum iron, transferrin saturation, ferritin, hepatic iron index and HFE gentoyping for C282Y and H63D mutations using genomic DNA samples. Of the 66 patients with HH, 91% were C282Y homozygotes, 3% compound heterozygotes (C282Y and H63D) and 1.5% and 3% were heterozygotes for C282Y and H63D respectively. In contrast, in the 132 OLD patients, 5% were C282Y homozygotes, 6% compound heterozygotes 5% were C282Y heterozygotes, 4% H63D homozygotes, 15% H63D heteroygotes and 66% were negative for both mutations. All 66 C282Y homozygotes had elevated hepatic iron concentration, 98% had transferrrin saturation > 45%. However, 10 (15%) had hepatic iron concentration < 1.9. In these, HH was not suspected until the genotyping. In the homozygous C282Y patients (n=19), no cirrhosis or significant fibrosis was seen in patients younger than 40 years. The authors conlcude that determination of HFE genotype is clinically useful in patients with chronic liver disease and HH can be diagnosed in otherwise unsuspected C282Y homozygote patients.