To evaluate the potential association betweenGSTM1andGSTT1genotypes and development of breast cancer, a hospital based case-control study was conducted in a South Korean study population consisting of 189 histologically confirmed incident breast cancer cases and their 189 age-matched control subjects with no present or previous history of cancer. A multiplex polymerase chain reaction method was used for the genotyping analyses and statistical evaluations were performed by unconditional logistic regression model. TheGSTM1null genotype was significantly associated with breast cancer risk in premenopausal women [odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1−3.7], but not in the postmenopausal women (OR = 0.9, 95% CI = 0.5−1.9), nor in all women grouped together (OR = 1.3, 95% CI = 0.8−1.1). TheGSTT1null genotype posed a similar risk of breast cancer with an OR of 1.6 (95% CI = 1.0−2.5) for the total breast cancer group, OR of 1.7 (95% CI = 0.9−3.2) for pre-menopausal women, and OR of 1.3 (95% CI = 0.6−2.8) for post-menopausal women. The breast cancer risk associated with concurrent lack of bothGSTM1andGSTT1genes was 2.2 (95% CI = 1.1−4.5), and the risk increased as the number of null genotype increased (Pfor trend = 0.03). When the data were stratified by the known risk factors of breast cancer, a significant interaction was observed between theGSTM1genotypes and alcohol consumption (Pfor interaction = 0.03). An especially remarkable risk of breast cancer was observed for alcohol-consuming premenopausal women lacking both theGSTM1andGSTT1genes (OR = 5.3, 95% CI = 1.0−27.8) compared to those with both of the genes. Our findings thus suggest a novel gene-environment interaction which plays an important role in the individual susceptibility to breast cancer.