The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in LPS-treated wt mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient Hjv-/- mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia only in control but not iron-loaded wt animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in Hjv-/- mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron induced liver ferroportin mRNA translation, thereby antagonizing hepcidin-mediated hypoferremia. Conversely, iron depletion suppressed de novo ferroportin synthesis in Hjv-/- livers, allowing exogenous hepcidin to cause hypoferremia. Consequently, prolonged LPS treatment eliminating ferroportin mRNA permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, liver ferroportin mRNA translation is critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data indicate a crosstalk between hepcidin/ferroportin and IRE/IRP systems. Moreover, they suggest that hepcidin supplementation therapy is more efficient combined with iron depletion.