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Because iron is both an essential and toxic micronutrient influencing the development of microbial infections, we evaluated the usefulness of iron parameters as outcome predictors in ICU patients.Prospective clinical single-center non-interventional study.General internal medicine ICU; German University hospital.One hundred and twelve septic and 43 nonseptic ICU patients, 156 healthy blood donors.Serum iron parameters at admission were correlated with short and long term mortality in ICU subjects. Both hepcidin and ferritin concentrations were significantly elevated in ICU patients compared with blood donors and were the highest in septic patients. On the contrary, serum iron and transferrin levels were decreased in ICU subjects with lowest values among septic patients. Hepcidin values correlated with ferritin levels, and serum iron correlated strongly with transferrin saturation. A moderate correlation of hepcidin, ferritin, and transferrin with inflammatory parameters was noted. Both short- and long-term survivors displayed higher ferritin/transferrin levels and lower transferrin saturation. In Kaplan-Meier analyses, low iron levels (cutoff 10.5 μmol/mL), low transferrin saturation (cutoff 55%), and high serum transferrin concentrations (cutoff 1.6 g/L) were associated with short- and long-term survival. In the subgroup of septic ICU subjects, low iron levels and transferrin saturation went along with a nonlethal outcome.Our findings demonstrate that parameters of iron metabolism, particularly transferrin saturation, that reflect serum iron availability, are strong outcome predictors in ICU patients. These data suggest that a failure of iron homeostasis with increased iron availability in serum occurs in lethally ill ICU patients and should trigger prospective clinical trials evaluating the usefulness of iron-chelating therapy in critical illness and sepsis.