BACKGROUND Recent data shows an increased mortality risk associated with elevated transferrin saturation. Because ingestion of dietary iron may contribute to iron overload in persons with elevated transferrin saturation, we investigated the relationship between elevated transferrin saturation, ingestion of dietary iron and red meat, and mortality. METHODS This 12-year cohort study used data from the second National Health and Nutrition Examination Survey 1976-1980 (NHANES II) and the NHANES II Mortality Study 1992. Population estimates were based on 9,229 persons aged 35 to 70 years at baseline. A Cox proportional hazards analysis was performed based on levels of transferrin saturation, intake of dietary iron, and intake of red meat. The analysis was conducted while controlling for demographics, severity of illness, body mass index, and smoking status. RESULTS Unadjusted analyses indicated that those who had a high transferrin saturation and reported high dietary iron or red meat consumption had an increased mortality risk. The adjusted survival analysis indicated that persons with elevated transferrin saturation who reported high dietary iron intake had a hazard ratio for death of 2.90 (95% confidence interval [CI], 1.39-6.04) compared with those with normal transferrin saturation levels and reported low dietary iron intake. Persons who had a high transferrin saturation and reported high red meat consumption also had an increased hazard ratio for death (2.26; 95% CI, 1.45-3.52) compared with those who had normal transferrin saturation and reported low red meat consumption. CONCLUSIONS Ingestion of large quantities of dietary iron and red meat in persons with high transferrin saturation is associated with an increase in mortality. Simple dietary restrictions may reduce the mortality risk associated with high transferrin saturation.