PURPOSE: The HEIRS Study screened 101,168 primary care participants for iron overload with serum transferrin saturation (TS), serum ferritin (SF), and C282Y and H63D mutations of the HFE gene. The objective of this study was to evaluate the impact of screening on participants' well-being. METHODS: All C282Y homozygotes, participants with an elevated TS and SF concentration, and a control group of phenotype-genotype negative persons, with neither C282Y nor H63D mutations in the HFE gene were recalled for a clinical evaluation. Health-related quality of life was assessed before screening and approximately 1 week after receipt of the results. Health worries were assessed only at follow-up. RESULTS: Participants (N = 1478) completed both initial and follow-up surveys. After adjusting for model covariates, phenotype and genotype combinations were statistically significant predictors of changes in psychological well-being (P = 0.0001) and general health (P = 0.0014). C282Y homozygotes with transient elevations in TS or SF were significantly more likely to worry about their health compared to study controls. Race, ethnicity, and preferred language subgroups differed on psychological well-being, general health, and health worry. CONCLUSION: Iron phenotype and HFE genotype are associated with health-related quality of life. Health worry was greatest among those considered genetically "at risk. " This may have important implications for multi-ethnic population-based screening studies in which genotype and phenotype are communicated. ©2007The American College of Medical Genetics.