INTRODUCTION: Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by abnormalities in hematopoietic stem cell. Many patients with MDS become transfusion therapy dependent and are prone to iron overload. The latter is caused by frequent transfusions and intrinsic characteristics of the disease. It is well known that HFE gene mutations (C282Y and H63D) lead to iron accumulation and cause hereditary hemochromatosis (HH). HFE gene mutations possibly affect disease course and prognosis of MDS. SUBJECTS AND METHODS: This research included 37 patients diagnosed with MDS in Clinical Hospital Dubrava, Zagreb, from 2008 to 2014. Patients were genetically tested for HFE gene mutations and effect of these mutations on iron metabolism parameters, overall survival (OS) and progression to leukemia were assesed. RESULTS: We have proved that C282Y mutation has significantly unfavourable effect on overall survival in patients with MDS. H63D mutation showes trend toward significance in OS when compared to wild type (wt) patients. We observed unfavourable effect of H63D mutation on MDS progression to leukemia frequency. HFE gene mutations incidence in healthy Croatian blood donors and in our patients does not differ significantly. Iron metabolism parameters analysis reveals that patients with H63D mutation have significantly lower TIBC levels and among them the transfusion naive patients have significantly higher ferritin levels. We did not observe statistically significant difference in other iron metabolism parameters. DISCUSSION: Our study found statistically insignificant difference in HFE mutations frequencies between healthy population and patients diagnosed with MDS. This observation is accordant with foreign authors' views and studies, as is our data that confirm evident effect of HFE mutations on iron metabolism. Probably the most notable finding of this study is the IV effect of HFE mutations on OS which is significantly worse in patients with mutated gene. These findings arouse dilemmas whether every MDS patient should be genetically tested for HFE mutations and whether earlier iron chelators therapy consideration in mutated patients is rational. CONCLUSION: A relative number of mutated individuals among MDS patients is higher than among healthy individuals but we were not able to prove statistically significant difference. HFE mutations have a poor effect on survival and progression to leukemia in MDS patients. Furthermore, HFE mutations' effect on iron parameters resulting in iron overload was noted.