BACKGROUND: There is evidence for increased mortality in patients with clinically overt hereditary hemochromatosis. Whether increased transferrin saturation (TS), as a proxy for iron overload is associated with increased mortality in the general population is largely unknown. METHODS: We examined mortality according to baseline TS in 2 Danish population-based follow-up studies (the Copenhagen General Population Study and the Copenhagen City Heart Study) comprising a total of 45 159 individuals, of whom 4568 died during up to 18 years of follow-up, and in a metaanalysis comprising the present studies and an additional general population study. RESULTS: In combined studies, the cumulative survival was reduced in individuals with TS ≥50% vs <50% (log-rank P < 0.0001). Multifactorially adjusted hazard ratios for total mortality for TS ≥50% vs <50% were 1.4 (95% CI 1.2-1.6; P < 0.001) overall, 1.3 (1.1-1.6; P = 0.003) in men, and 1.5 (1.1-2.0; P = 0.005) in women. Results were similar if the 2 studies were considered separately. A stepwise increased risk of total mortality was observed for stepwise increasing levels of TS (log-rank P < 0.0001), with the highest risk conferred by TS ≥80% vs TS <20% with a hazard ratio of 2.2 (1.4-3.3; P < 0.001). The population-attributable risk for total mortality in the combined studies in individuals with TS ≥50% vs <50% was 0.8%. In metaanalysis, the odds ratio for total mortality for TS ≥50% vs <50% was 1.3 (1.2-1.5; P < 0.001) under the fixed-effects model. CONCLUSIONS: Individuals in the general population with TS ≥50% vs <50% have an increased risk of premature death.