To determine whether release of tumor necrosis factor-alpha (TNF-alpha), a cytokine that affects iron homeostasis, may be selectively altered in hereditary hemochromatosis, we measured concentrations of TNF-alpha and interleukin-1 beta (IL-1 beta) in supernatants of cultured peripheral blood monocytes from 11 homozygotes for hereditary hemochromatosis, 11 healthy individuals, and five patients with iron-loading anemia. The gene for hereditary hemochromatosis is tightly linked to the HLA locus on chromosome 6, but its exact site and product are not known. The gene for TNF-alpha also is located within the HLA region. Monocytes were incubated from 4 to 36 hours in medium alone or with added lipopolysaccharide. Mean concentrations of immunoreactive TNF-alpha in supernatants were significantly lower for subjects with hereditary hemochromatosis as compared to healthy controls (P less than .037) and patients with iron-loading anemia (P less than .005); differences between homozygotes for hemochromatosis and healthy controls were up to 4.5-fold at 4 hours (P = .008), 1.9-fold at 12 hours (P = .036), and 7.0-fold at 36 hours (P = .001). Importantly, concentrations of IL-1 beta in supernatants were not significantly different among the three groups. We conclude that release of TNF-alpha by monocytes may be selectively impaired in hereditary hemochromatosis. Deficient activity of TNF-alpha may contribute to the disordered iron metabolism of this disease.