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OBJECTIVE--It is not known to what extent iron overload predicts prognosis in patients with diabetes after diagnosis or whether iron overload is a risk factor independent of the geno-HFE type. We investigated total and cause-specific mortality according to increased transferrin saturation (≥50 vs. <50%), whether mortality is driven by the genotype, and whether early HFE measurement of transferrin saturation helps to predict mortality outcome. RESEARCH DESIGN AND METHODS--Cohort 1 included patients with late-onset type 1 diabetes (n = 716) with a cross-sectional measurement of transferrin saturation and HFE genotype. Cohort 2 included consecutively recruited patients with any diabetes (n = 6,120), transferrin saturation measurement at referral, and genotype if transferrin saturation HFE was above 50%. RESULTS--In cohort 1, the hazard ratio for total mortality was 2.3 (95% CI 1.3-3.9; P = 0.002) and for cause-specific mortality by neoplasms was 5.8 (2.4-14; P = 0.00007) in patients with transferrin saturation ≥50 vs. <50%. Excluding genotypes C282Y/C282Y and C282Y/H63D gave similar results. The hazard ratio for total mortality was 4.0 (1.2-13; P = 0.01) and for cause-specific mortality by neoplasms was 13 (3.6-49; P = 0.0001) in patients with C282Y/C282Y versus wild type. In cohort 2, total mortality was not different in patients with transferrin saturation ≥50 vs. <50%. In patients with late-onset type 1 diabetes and transferrin saturation ≥50%, the hazard ratio for total mortality was 0.4 (0.2-0.9; P = 0.03) in cohort 2 versus cohort 1. CONCLUSIONS--Increased transferrin saturation and genotype C282Y/C282Y predict HFE total mortality in patients with late-onset type 1 diabetes, and increased transferrin saturation after diagnosis is an independent risk factor. Early measurement of transferrin saturation in these patients leading to early intervention improves life expectancy. [ABSTRACT FROM AUTHOR]