Background: Myelodysplastic syndromes are a heterogeneous group of disease of pre-leukemic nature and variable natural history and prognosis. MDS were repeatedly investigated and re-classified over time. Nucleophosmin is a commonly investigated molecular marker due its role in pathogenesis of AML. Aim of the Work: to investigate the prognostic value of nucleophosmin exon 12 mutation (NPM mutA) in adult patients with de novo MDS and normal karyotype. Subjects and Methods: Study was carried out on 30 subjects divided into 2 groups: 20 patients with de novo MDS and normal karyotype, and 10 healthy volunteers. Investigation of NPM mutA was done using conventional RT-PCR followed by agarose gel electrophoresis. Results: Nucleophosmin exon 12 mutation A was restricted to adult patients with de novo MDS and normal karyotype (2 out of 20, 10%). It was restricted to patients with intermediate risk of progression to AML, both classified as RAEB. None of these patients had a disease that progressed to AML during study. Conclusions: NPM1 mutA may be a favorable early molecular event that confers some protection against evolution of AML, and, thus, might be a good prognostic factor in a disease that lies on the verge of AML, but this needs to be confirmed with further studies on large cohorts.