Polymorphisms of xenobiotic-metabolizing genes correlate with hereditary predisposition to neoplasia in some cases. The frequencies of polymorphisms of xenobiotic-metabolizing genes were determined in 332 children with acute lymphoblastic leukemia, 71 children with acute myelogenous leukemia, and 490 healthy donors by allele-specific hybridization on a biochip. The frequencies of the GSTT1 null genotype and the GSTT1/GSTM1 double null genotype were significantly increased in children with acute leukemia as compared to healthy donors (OR = 1.9, P = 4.7E-5, and OR = 3.1, P = 2.5E-8, respectively). The frequency of NAT2 genotype 341T/T, 481C/C, 590G/G was increased 1.8-fold in children with acute leukemia as compared to healthy controls (P = 0.026). Analysis of gene-gene interactions showed that the combination of NAT2 genotype 341T/T, 481C/C, 590G/G with the GSTT1 and/or GSTM1 null genotypes was significantly more frequent in patients with acute leukemia than in the population control. In addition, the frequency of MTRR genotype 66G/G was reduced in girls with acute leukemia as compared to healthy female donors (OR = 0.50, P = 0.0015). The GSTT1 and/or GSTM1 null genotypes combined with MTRR genotype 66A/-were considered to be a risk factor for acute leukemia in girls. Thus, the polymorphisms of GSTT1, GSTM1, NAT2, and MTRR proved to influence the risk of childhood acute leukemia in residents of European Russia.