Mutations of HFE are associated with hereditary hemochromatosis, but their influence on host susceptibility to infection is incompletely understood. We report that mice lacking one or both Hfe alleles are protected from septicemia with Salmonella Typhimurium, displaying prolonged survival and improved control of bacterial replication. This increased resistance is paralleled by an enhanced production of the enterochelin-binding peptide lipocalin-2 (Lcn2), which reduces the availability of iron for Salmonella within Hfe-deficient macrophages. Accordingly, Hfe^−/−Lcn2^−/− macrophages are unable to efficiently control the infection or to withhold iron from intracellular Salmonella. Correspondingly, the protection conferred by the Hfe defect is abolished in Hfe^−/− mice infected with enterochelin-deficient Salmonella as well as in Hfe^−/−Lcn2^−/− mice infected with wild-type bacteria. Thus, by induction of the iron-capturing peptide Lcn2, absence of functional Hfe confers host resistance to systemic infection with Salmonella, thereby providing an evolutionary advantage which may account for the high prevalence of genetic hemochromatosis.