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The glutathione-S-transferase (GST) family contributes to the inactivation of various toxic compounds formed as secondary metabolites during oxidative stress. GSTP1 accounts for the majority of the GST family enzymatic activity, and the activity of GSTP1 enzyme can be altered by the presence of the Ile105Val polymorphism. In this study, we examined the polymorphic frequency of GSTP1 Ile105Val genotype in 920 breast cancer patients and 783 healthy controls in women of North China. Results showed that GSTP1 105Val allele (Ile/Val and Val/Val) was associated with a higher breast cancer risk (OR = 1.38, 95% CI: 1.14–1.69; P = 0.001) and more aggressive tumors with histological grade III (OR = 1.15, 95% CI: 1.05–1.26; P = 0.001), lymph node metastases (OR = 2.35, 95% CI: 1.72–3.21; P < 0.001), as well as ER negative (OR = 1.77, 95% CI: 1.31–2.39; P < 0.001) than those carrying the Ile/Ile allele. However, the patients with the GSTP1 105Val genotype had a better disease free survival after cyclophosphamide (CTX)-based chemotherapy than those with Ile/Ile (HR = 0.77, 95% CI: 0.45–0.91; P < 0.001). Furthermore, in vitro cellular experiments demonstrated that breast cancer cells with the GSTP1 105Val allele were significantly more sensitive to CTX-induced proliferation inhibition. Thus, we conclude that the GSTP1 105Val allele increases breast cancer risk and aggressiveness and enhance response to CTX-based chemotherapy in women of North China. Detection of the GSTP1 Ile105Val genotype may help screen for high-risk populations and direct individualized therapy. [ABSTRACT FROM AUTHOR]