As a general rule, an important factor in determining iron toxicity is represented by the route by which the element enter the body, which in turn is unable to excrete excess iron. The parenteral route, i.e. through RBC transfusions, leads to prominent macrophage iron overload that tends to be better tolerated than the intestinal route, leading to prominent overload in periportal hepatocytes and thereafter in other parenchymal cells. Given its pivotal role in orchestrating both iron absorption and recycling from macrophages, hepcidin has been an attractive candidate for studying perturbed iron homeostasis in MDS, but few and contradictory data have been available until now. Winder and colleagues studied 16 MDS patients 13 of them chronically transfused and found undetectable or inappropriately low urinary hepcidin in most of them. These Authors suggested that hepcidin suppression through increased erythropoietic drive, and the ensuing increased iron absorption may be generalized phenomena in MDS. Murphy and colleagues were unable to confirm these data in 17 low grade MDS patients, most of them showing normal, if not increased, urinary hepcidin levels. Besides the very limited patients series, both these studies suffered from methodological drawbacks, since they employed first Tofacitinib generation semi-quantitative assays of urinary hepcidin that have been abandoned because of insufficient precision. To the best of our knowledge this is the largest study on hepcidin levels in MDS conducted so far. Moreover, it takes advantage from the use of a validated quantitative MS-based assay, recently further improved. Contrary to the prior hypothesis of a generalized hepcidin suppression, the main message from our data is that hepcidin production in MDS is consistently heterogeneous, a condition that appears to parallel the clinical and pathological heterogeneity of MDS by themselves. This is also in agreement with in vitro experiments showing a marked variability of sera from MDS patients in their ability to suppress hepcidin in a hepatocyte cell line. The spectrum of hepcidin levels varied broadly from conditions with mean levels less than a half of those in controls, like RARS, to other ones with mean levels more than twice of controls, like RAEB and CMML. As regards to the homeostatic control of hepcidin by iron, a similar heterogeneity was evident. Although the hepcidin/ ferritin ratio showed a generalized trend toward a relatively inappropriate response, the homeostatic control by iron appeared relatively conserved in MDS subtypes generally considered at low risk.