Iron metabolism might be involved in the pathogenesis of CAD, and C282Y and H63D mutations in the HFE gene are associated with increased serum iron levels and net iron accumulation. The aim of this study was to look for a relationship between the C282Y and H63D gene mutations of the HFE gene and coronary artery disease (CAD) in a group of patients with type 2 diabetes lasting more than 10 years. The C282Y and H63D gene mutations were tested in 338 Caucasians with type 2 diabetes: 156 cases with CAD and 182 subjects with no history of CAD. The C282Y and the H63D HFE gene distributions in patients with CAD (C282Y: YY 0.6%, CY 9.0%, CC 90.4%; H63D: DD 3.8%, HD 21.8%, HH 74.4%) were not significantly different from those of diabetic subjects without CAD (C282Y: YY 0%, CY 8.2%, CC 91.8%; H63D: DD 2.2%, HD 20.3%, HH 77.5%). In conclusion, we failed to demonstrate that the C282Y and H63D HFE gene mutations were risk factors for CAD in Caucasians with type 2 diabetes lasting longer than 10 years.