BACKGROUND A population-based hemochromatosis screening program that uses serum transferrin saturation has been proposed, but few data exist on the number of U.S. adults that such a program would identify for further testing. OBJECTIVE To determine the prevalence of an initially elevated serum transferrin saturation and the prevalence of concurrently elevated serum transferrin saturation and serum ferritin levels in the adult population of the United States. METHODS Nationally representative cross-sectional survey of the noninstitutionalized U.S. civilian population. METHODS 15 839 men and nonpregnant women 20 years of age and older who were examined in the third National Health and Nutrition Examination Survey (1988-1994). METHODS Single measurements of serum transferrin saturations and serum ferritin levels. Cut-off values used to define elevated serum transferrin saturation ranged from greater than 45% to greater than 62%. RESULTS The prevalence of initially elevated serum transferrin saturation ranged from 1% to 6%. Approximately 11% to 22% of those with elevated serum transferrin saturation had concurrently elevated serum ferritin levels. The prevalence of elevated serum transferrin saturation was lower in women than in men when the same cut-off value was used to define elevated serum transferrin saturation. The prevalence of elevated serum transferrin saturation in non-Hispanic black persons and Mexican-Americans was similar to or slightly less than that in non-Hispanic white persons. The prevalence of elevated serum transferrin saturation in persons 20 to 49 years of age was as high as or higher than that in older adults. CONCLUSIONS A hemochromatosis screening program that uses a cut-off value of greater than 60% to define elevated serum transferrin saturation would identify an estimated 1.4 to 2.5 million U.S. adults for further testing.