Genetic hemochromatosis (GH) is an iron overload disorder mainly due to the C282Y mutation of the HFE gene. The possibility of bone involvement was only recently recognized. The aims of this study were to assess bone mineral density (BMD) and bone remodeling in men with GH, and to examine the influence of iron overload. Thirty-eight men (mean age 47.2+/-9.4 years) with well-defined HFE-related GH were studied. They had an important iron overload with liver iron concentration to age ratio >2.5, no previous venesection therapy and were C282Y homozygotes (n=37) or compound C282Y/H63D heterozygote (n=1). BMD measured by DXA was 0.925+/-0.15 g/cm2 at the lumbar spine (LS) and 0.778+/-0.13 g/cm2 at the femoral neck (FN). Osteopenia (T-score<-1 SD) was observed in 78.9% of patients and osteoporosis (T-score<-2.5 SD) in 34.2%. Vitamin D levels were normal, and no 1-84 parathyroid hormone dysfunction was found. Hypogonadism was found in only 13.2% of patients. Patients with hypogonadism had lower LS BMD than eugonadal patients (0.788+/-0.16 and 0.954+/-0.14 g/cm2). Bone remodeling and parathyroid hormone levels were lower in patients with cirrhosis, but BMD values were similar to those in patients without cirrhosis. FN BMD appeared to fall with rising hepatic iron concentrations (r=-0.399). We conclude that there is significant bone loss in HFE-related hemochromatosis that cannot solely be explained by hypogonadism or cirrhosis. Further investigations are needed to determine the role of iron overload itself.