Heavy iron loading is a rare clinical finding in patients with hereditary spherocytosis. A pedigree was studied in which the proband, a 38-year-old man, had both hereditary spherocytosis and overt hemochromatosis. He had never received blood transfusions. The 8-year-old son of the proband also had hereditary spherocytosis and mildly increased iron stores. The 39-year-old brother of the proband did not have spherocytosis but did have overt hemochromatosis. Since hemochromatosis is transmitted as an HLA-linked autosomal recessive disorder, HLA haplotypes serve as markers of hemochromatosis alleles. In this pedigree only individuals with two hemochromatosis alleles (homozygosity) had heavy iron loads, whether hereditary spherocytosis was present or not. The presence of hereditary spherocytosis may have contributed to the magnitude of the iron loading but was not a major factor. Our findings suggest that nontransfusional hemochromatosis found in association with hereditary spherocytosis is due primarily to homozygosity for hemochromatosis.