Summary. Most features of C282Y-linked haemochromatosis support the implementation of population screening of the disorder in Caucasians. However, the penetrance of C282Y homozygosity is poorly documented and the strategy for population screening remains debated. Nine thousand three hundred and ninety-six subjects (3367 men, aged 25–40 years, and 6029 women, aged 35–50 years), attending three Health Appraisal Centres, were genotyped and assessed with respect to clinical and biochemical signs of haemochromatosis. Discriminant, logistic regression and graphic analysis were used to predict homozygosity. Results were validated in 135 homozygotes detected through other family and population studies. Fifty-four subjects (10 men and 44 women) were homozygous for C282Y. All men had abnormal iron status and most had mild clinical symptoms compatible with haemochromatosis. Identification of all homozygous men required a transferrin saturation (TS) threshold of 50% in the study group (90% specificity) and of 40% in the validation group. Homozygous women differed clinically from non-homozygotes for the presence of distal arthralgias only (18%vs 6%, P < 0·03). Thirteen (29%) were iron-deficient (serum ferritin < 13 µg/l) and undetectable by biochemical tests. Although the population studied was not fully representative of the general population, our data strongly suggests that, in young men, large-scale screening for C282Y homozygosity is justified and can be achieved by using TS prescreening. However, in premenopausal women, large-scale screening remains to be justified with respect to the natural history of haemochromatosis and should be directly genotypic.