Iron metabolism is tightly regulated so that iron is available for core biological functions while preventing its cytotoxic effects. Macrophages play a central role in establishing this delicate balance. Kupffer Cells (KCs), the liver resident macrophages, serve notably a major role in the elimination of damaged red blood cells. Such function ensures systemic iron recycling to prevent damage from excess iron, heme, and hemoglobin deposition in organs. Moreover, the hepcidin (HAMP)/ferroportin (FPN1) axis is critical to coordinate cellular iron export. Hepcidin induces the degradation of the iron exporter ferroportin, thereby suppressing cellular iron release from macrophages and parenchymal cells. Whereas it is well established that hepatocyte-derived hepcidin controls systemic iron homeostasis, the autocrine role of hepcidin produced by the macrophage remains to be more defined. Here, we observed that iron overloading by iron dextran injection into wild-type mice resulted in a rapid (2 days) and partial loss of embryonically-derived KCs (i.e. EmKCs composing the KC pool in healthy livers). Concomitantly, monocyte-derived macrophages were recruited to the liver and acquired the prototypical KC marker CLEC2. However, engraftment of these monocyte-derived KCs was only transient, and EmKCs proliferated to replenish the KC pool later (15 days). Similar studies of iron overloading were replicated in mice with hepcidin deficiency in macrophages (Lysm-Cre x Hampl^ox/lox), including KCs. Decreased EmKCs density was rapidly observed in both Lysm-Cre x Hamp^lox/lox and Hamp^lox/lox control mice following iron dextran injection. However, 2 weeks later, EmKCs in Lysm-Cre x Hamp^lox/lox mice exhibited both, a reduced proliferation rate and a diminished pool as compared to control mice. These preliminary observations support the contention that hepcidin, in an autocrine way, plays a role in Kupffer Cells’ response to iron overloading.