Hereditary hemochromatosis (HH), an iron overload disease caused by unregulated intestinal iron absorption, is a recessive HLA-linked disease. HH is the most common inherited metabolic disorder with one of every 400 to 500 individuals having both genes and being likely to develop the disease. Thus, although the product of the hemochromatosis gene is unknown, its mode of inheritance allows HLA-genotyping of the proband and his/her siblings to be highly predictive of the genetic propensity to develop the clinical features of HH. In view of the known immunoregulatory properties of iron and its binding proteins, it is important to determine if the high levels of storage iron in HH influence the immunosurveillance network in HH patients and whether that has any clinical relevance. We have defined certain alterations of the effector cells of the cellular arm of the immune system and have studied a patient with HH who had specific immune alterations, including delayed cutaneous-type hypersensitivity anergy, and was diagnosed with poorly differentiated adenocarcinoma of the stomach four years after his HH diagnosis. Those findings are consistent with the interpretation that in certain clinical situations of elevated body iron stores, the immunoregulatory balance or environment may be tipped in favor of growth and development of cancer cells.