The work studied possible association between genetic polymorphisms of CYP2D6, GSTM1, GSTT1and NQO1 and altered susceptibility to leukaemia, correlating these genetic polymorphisms with clinical prognostic data, response to therapy and relapse. The study included 32 leukaemia patients, 19 with acute myeloid leukemia (AML) and 13 with acute lymphoid leukaemia (ALL), and 11 normal individuals (control group). Basic investigations for the diagnosis of AML and ALL were performed, including blood picture, bone marrow aspirate, cytochemistry and immunophenotyping for detection of subtypes. Detection of CYP2D6, NQO1, GSTM1 and GSTT1 genetic polymorphisms used a polymerase chain reaction-restriction fragment length polymorphism. A follow-up was made for association between the outcome of patients and different patterns of genetic polymorphisms. Results demonstrate a significant increase in the frequency of CYP2D6 wild-type and GSTM1 null genotypes in the acute leukaemia group compared with the control. Studying the relationship between polymorphisms of these genes and the outcome of our cases revealed the wild genotype of CYP2D6 significantly influenced the outcome of acute leukaemia particularly in AML cases, while GSTM1 null genotype was associated with bad prognosis among the ALL group. The study also revealed that patients with combined mutant CYP2D6/present GSTM1/present GSTT1 achieved the best prognosis, suggesting synergistic impact of these genetic polymorphisms on the outcome of acute leukaemia cases. This case-control study suggests a contribution of CYP2D6 and GSTM1 null variants in the development of acute leukaemia. In addition, GSTM1 and GSTT1 genotypes were apparently related to response, side effects and prognosis of patients with AML.