The clinical experience of the significant difference in iron metabolism between multiple myeloma and myelodysplasia prompted us to analyse patients according to mutation frequency in the hemochromatosis gene (HFE) known to participate in the regulation of iron metabolism. HFE genotyping results were also evaluated in view of the clinical data in multiple myeloma (MM) patients. 49 patients with MM were compared to 61 patients with myelodysplastic syndrome (MDS) concerning the incidence of two genetic variants of the HFE gene (C282Y and H63D) identified with PCR-RFLP. Data of serum iron, transferrin saturation, consumed blood units and initial white blood cell counts (WBC) were analysed in relation to the HFE genotype status. 30 out of the 61 MDS patients (49%) and only 9 out of the 49 MM patients (20%) were positive for either HFE variant. Serum iron and transferrin saturation levels were all normal in MM and elevated in MDS patients. The initial WBC were significantly lower in the minority of MM patients who were at the same time heterozygous for the HFE gene variants. We found significant differences in the frequencies of the HFE genetic variants between MDS and MM patients with strong correlation to their iron metabolism. The low WBC in HFE positive MM patients unrelated to bone marrow infiltration rate might raise the suspicion of co-existent myelodysplasia.