GSTM1 and GSTT1 are polymorphic genes. Absence of enzyme activity is due to homozygous inherited deletion of the gene, reducing detoxification of carcinogens such as epoxides and alkylating agents and potentially increasing cancer risk. We hypothesized that GST null genotype would increase risk of acute myeloid leukemia and myelodysplasia (AML/MDS) in children. DNA was extracted from bone marrow slides of 292 AML/MDS patients. PCR amplification was used to assign GSTM1 and GSTT1 genotypes for cases and controls. Given that the frequency of the null genotype varies by ethnicity and that the majority of the cases were Caucasian, analyses were restricted to 232 white (non-Hispanic) cases and 153 Caucasian non cancer controls. The frequency of GSTM1 null was significantly increased in AML/MDS cases compared with controls [64 versus 47%; odds ratio (OR), 2.0 [95% confidence interval (CI), 1.3-3.1]; P = 0.001], whereas the frequency of GSTT1 null genotype in AML/MDS cases was not statistically different from controls. AML comprises biologically distinct subtypes, and a test for homogeneity revealed a statistically significant difference among subtypes (P = 0.04; df, 8) for GSTM1 only. In particular, there was an increased frequency of GSTM1 null genotypes in French-American-British groups M3 [82%; n = 22; OR, 5.1 (95% CI, 1.6-21.3)] and M4 [72%; n = 53; OR, 2.9 (95% CI, 1.4-6.0)]. We conclude that the GSTM1 null genotype is a significant risk factor for childhood AML, particularly French-American-British groups M3 and M4. This may indicate an important role for exogenous carcinogens in the etiology of childhood AML.