Lack of either BMP6 or the BMP co-receptor hemojuvelin (HJV) in mice leads to a similar phenotype with hepcidin insufficiency, hepatic iron loading, and extrahepatic iron accumulation in males. This is consistent with the current views that HJV is a co-receptor for BMP6 in hepatocytes. To determine whether BMP6 and HJV may also signal to hepcidin independently of each other, we intercrossed Hjv-/- and Bmp6-/- mice and compared the phenotype of animals of the F2 progeny. Loss of Bmp6 further repressed Smad signaling and hepcidin expression in the liver of Hjv-/- mice of both genders, and led to iron accumulation in the pancreas and the heart of females. These data suggest that, in Hjv-/- females, Bmp6 can provide a signal adequate to maintain hepcidin to a level sufficient to avoid extrahepatic iron loading. We also examined the impact of Bmp6 and/or Hjv deletion on the regulation of hepcidin by inflammation. Our data show that lack of one or both molecules does not prevent induction of hepcidin by LPS. However, BMP/Smad signaling in unchallenged animals is determinant for the level of hepcidin reached after stimulation, which is consistent with a synergy between IL6/STAT3 and BMP/SMAD signaling in regulating hepcidin during inflammation.