Hereditary Haemochromatosis is an iron overload disorder associated with mutations in the HFE gene, and to a lesser degree, the gene encoding its chaperone protein beta-2 microglobulin (beta 2M). Here, we report that knockdown of beta 2M by RNAi restricts HFE distribution to the endoplasmic reticulum (ER). Additionally, we demonstrate that hepcidin, an iron homeostasis-associated protein, localises predominantly to LBPA-positive late endosomes. Interestingly, we show that knockdown of beta 2M by RNAi perturbs hepcidin localisation to late endosomes. In summary, our data suggest that beta 2M is essential for the correct subcellular distribution of both HFE and hepcidin, two proteins, which are critical for iron homeostasis. (C) 2008 Elsevier Inc. All rights reserved.