OBJECTIVE The high prevalence, morbidity, premature death, and benefit of early diagnosis and treatment make hemochromatosis a prime target for screening in the white population. Decision analysis techniques were used to compare the outcome, utility, and incremental cost savings of a plan to screen voluntary blood donors for hemochromatosis. METHODS The screening strategy includes sequential testing of serum unsaturated iron-binding capacity, serum transferrin saturation, serum ferritin, and either hepatic iron index or venesections to measure exchangeable body iron. Estimates of prevalence, asymptomatic intervals, probabilities of life-threatening clinical complications, symptom-specific life expectancy, and sensitivity and specificity of screening tests are based on our database of 170 hemochromatosis homozygotes and the published literature. RESULTS The screening strategy led to an incremental increase in utility of 0.84 quality-adjusted life days with an incremental cost savings of $3.19 per blood donor screened. When the potential of identifying asymptomatic homozygous siblings was included, these values increased to 1.18 quality-adjusted life days and $12.57 per person screened. Screening remained a dominant strategy given a prevalence of hemochromatosis of > 0.0026 or an initial screening test cost of < $8. CONCLUSIONS Screening blood donors for hemochromatosis has the potential to improve overall societal health status and decrease third-party payer health care costs over the long-term.