Hematological malignancies are clonal diseases that develop due to the genetic aberration in a single hematopoietic cell in bone marrow or lymphoid tissue. The mechanism of this clonal aberration is not completely understood, but it is known to be caused by the combined effects of genetic factors and environmental influences. Clonal aberrations are result of the accumulation of inherited and acquired somatic mutations in proto-oncogenes and tumor suppressor genes. The third class of genes is the DNA reparation genes, which inactivation initiates clonal expansion due to the increased cell survival and proliferation. The NQO1 gene product participates in a metabolic process of detoxification of potential chemical carcinogens, whereas the NBS1 gene product participates in DNA reparation, thus both having the protective effects on hematopoietic cells. In our study we investigated genetic aberrations (polymorphism and deletional mutation) in two constitutional genes, NQO1 and NBS1. We investigated C609T polymorphism of the NQO1 gene and 657del5 mutation of the NBS1 gene in 82 patients with different hematopoietic malignancies and 99 healthy participants using standard methods. For detection of C609T polymorphism, we performed polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) after Hifn1 digestion. The products were visualized on agarose or polyacryamide gels. For detection of 657del5, we performed PCR with PCR-product visualization of high resolution polyacryamide gen (to distinguish between 5 base pair difference between PCR-products). We confirmed that the NQO1 gene C609T polymorphism, with T/T and T/C genotypes, significantly more frequent in the patients’ group (39%) compared with the healthy participants (21%) (p = 0.031, χ 2). The significant difference, with the increased likelihood (risk) (odd ratio = 2.4) of developing hematopoietic malignancy, was found in the group of adult (mostly elderly) patients with myeloid disorders (p=0.026, χ 2). Also, we analyzed clonal karyotype aberrations in patients in relation to the presence of NQO1 gene C609T polymorphism. Nevertheless, we could not confirm the significant difference regarding the frequency of C609T polymorphism, with T/T or C/T genotypes, between patients with the specific cytogenetic clonal aberrations in karyotype (41/77) and those with the normal karytype (36/77). Furthermore, we found the presence of the NBS1 gene 657del5 Slavic mutation in 2 out of 82 patients’ samples. This deletional mutation was not detected in the control group, therefore we believe that it could be important for leukemogenesis, particularly because disease developed in early age- in a boy (657del5/657del5) with MDS and a girl (657del5/N) with ALL. We could not analyze and evaluate the importance of the combined (multiple) genotype aberrations for the pathogenesis of hematopoieticl malignancies considering only two patients with the NBS1 gene 657del5 Slavic mutation, which was not accompanied neither with the NQO1 gene C609T polymorphism (C/T or T/T) nor with the karyotype clonal aberrations. Our study revealed that both of the analyzed genotype aberrations have a role in the pathogenesis of hematopoietic clonal malignancies. Further research should reveal the role of other genes in maintaining the stability of the genome of the hematopoietic stem cell, and the interaction of those genes with the environmental factors.