There has been much interest in screening populations for disease-associated mutations. A favored candidate has been the HFE gene, mutations of which are the most common cause of hemochromatosis in the European population. About five people in 1000 are homozygotes for the 845G3 A mutation, but little is known of how many have mutation-caused clinical manifestations. We screened 41038 individuals attending a health appraisal clinic in the USA for the 845G3 A and 187C3 G HFE mutations, and analysed laboratory data and data on signs and symptoms of hemochromatosis as elicited by questionnaire. The most common symptoms of hemochromatosis, including poor general health, diabetes, arthropathies, arrhythmias, impotence, and skin pigmentation were no more prevalent among the 152 identified homozygotes than among the controls. The age distribution of homozygotes and compound heterozygotes did not differ significantly from that of controls: there was no measurable loss of such individuals from the population during ageing. However, there was a significantly increased prevalence of a history of hepatitis or "liver trouble" among homozygotes and in the proportion of homozygotes with increased concentrations of serum aspartate aminotransferase and collagen IV; these changes were not related to iron burden or to age. Only one of the 152 homozygotes had signs and symptoms that would suggest a diagnosis of hemochromatosis. The normal age distribution of people with the hemochromatosis genotype, and the lack of symptoms in patients of all ages, indicate that the penetrance of hereditary hemochromatosis is much lower than generally thought. The clinical penetrance of a disorder is an essential consideration in screening for genetic disease; disorders with low penetrance are more expensive candidates for screening than disorders with high penetrance. Our best estimate is that less than 1% of homozygotes develop frank clinical hemochromatosis.