Approximately 85% of patients with typical hereditary hemochromatosis (HH) are homozygous for the C282Y mutation (C282Y/C282Y) in the recently identified candidate gene for HH. However, some HH patients are instead homozygous for the wild-type allele (wt/wt) at this locus. These wt/wt patients may represent a phenotypically similar, but genotypically different, heritable trait, or may be unrecognized cases of secondary iron overload. The purpose of this study is to provide an in-depth analysis of the wt/wt HH patients identified in the original description of the HH gene, and to compare them with 62 patients from the same analysis who were homozygous for the C282Y mutation. Eighteen of the 21 wt/wt HH patients from the original study were assessed for 14 historical and laboratory variables, including previously unrecognized causes of secondary iron overload, the heritability of iron overload and liver disease, and other clinical characteristics. Ten of these 18 wt/wt HH patients (55.6%) were found to have previously unrecognized causes for secondary iron overload compared with 3 of 62 (4.8%) of the C282Y/C282Y patients (P < .001). The remaining 8 wt/wt patients had no recognizable etiology of secondary iron overload. None of the 18 wt/wt patients had a family history of iron overload or liver disease, compared with 58% of the C282Y/C282Y patients (P < .001). When compared with C282Y homozygotes, the 8 wt/wt patients without secondary iron overload had a higher presenting hepatic iron index (HII) (9.5 vs. 4.7; P = .01). We conclude that, in this series of patients, over half of the wt/wt HH patients possessed previously unrecognized causes of secondary iron overload, and therefore, may have been misdiagnoses. If these cases are excluded, the number of false-negative tests is decreased, and the sensitivity of the mutational analysis is increased. However, there is a subgroup of wt/wt patients who have typical hemochromatosis without an identifiable cause of secondary iron overload. These patients may have more severe iron loading than C282Y homozygotes.