The objective of the paper was to study the association of polymorphisms of phases I and II xenobiotic metabolizing enzyme genes cytochrome P450 (CYP-4501A1*2A, *2B, *2C and *4 alleles, CYP-4502D6*4 allele), glutathione-S-transferase (GSTM1 and GSTT1 null genotypes) and N-acetyl transferase 2 (NAT2*6B and *7A alleles) with the incidence of acute myeloid leukemia (AML) in an eastern Indian population. Polymerase chain reaction and restriction fragment length polymorphism of genomic DNA from peripheral blood cells were used to detect CYP-450 and NAT2 gene polymorphisms in 110 AML patients and 144 racially and geographically matched normal controls. Polymerase chain reaction was also applied to detect GST gene polymorphisms in both groups. A statistically significant difference between the AML group and the normal group was observed in the case of glutathione-S-transferase M1 null (odds ratio 3.25, 95% confidence interval 1.9-5.58, P<0.001) and N-acetyl transferase 2*6B (odds ratio 3.04, 95% confidence interval 1.79-5.16, P<0.001) genotypes. Combined deficiency of N-acetyl transferase 2 and glutathione-S-transferase M1 genes produced an odds ratio of 11.91 (95% confidence interval 4.06-34.96, P<0.001). The effect of N-acetyl transferase 2*6B (P<0.001) is significant only at ages ≤40. In the population studied, persons with glutathione-S-transferase M1 null genotype and N-acetyl transferase 2*6B allele are at increased risk of developing AML, and the risk is considerably enhanced in persons with both glutathione-S-transferase M1 and N-acetyl transferase 2 deficiency. © 2008 Lippincott Williams & Wilkins, Inc.