Objectives: We sought to evaluate the hypothesis that the relatively high HFE C282Y allele frequency in White persons in central Alabama (0.0896) is due to a predominance of persons of Irish and Scots descent, and is not attributable to Native American ancestry common in this geographic area. Design: Eighty evaluable hemochromatosis probands with C282Y homozygosity and 319 White controls reported countries of ancestry of their grandparents. Frequencies of country of ancestry reports were tabulated. The reports were also converted to scores that reflect proportional countries of ancestry in individuals. Using the scores, we computed aggregate country of ancestry indices as estimates of group ancestry composition. Results were compared to those of European populations with C282Y allele frequencies >0.0800. Results: The respective frequencies of "British Isles" and Scotland reports were significantly greater in hemochromatosis probands than in controls. The respective frequencies of "Europe Not British Isles," Italy, and Poland reports were significantly greater in controls. Aggregate "British Isles" and Scotland indices were significantly greater in hemochromatosis probands. The "Europe Not British Isles" index was significantly greater in controls. Approximately one-quarter of hemochromatosis probands and controls reported "Native American" ancestry; the corresponding country of ancestry index was not significantly different in probands and controls. C282Y frequencies >0.0800 were reported from England, Ireland, Scotland, Wales, Brittany, and Denmark. Conclusions: The present results indicate that hemochromatosis probands with C282Y homozygosity in central Alabama report significantly different countries of ancestry than control subjects. It is unlikely that Native American ancestry is associated with an enrichment of hemochromatosis among adult probands. British Isles ancestry, not exclusively Irish and Scots ancestries, likely accounts for the relatively high C282Y frequency in White persons in central Alabama.