NRF2 activates several protective genes, such as sulfiredoxin (SRXN1), as a response to oxidative and xenobiotic stress. Defects in NRF2 pathwaymay increase cancer susceptibility. In tumor cells, activation of NRF2may lead to chemoand radioresistance and thus affect patient outcome. Nine single-nucleotide polymorphisms on NRF2 gene and eight on SRXN1were genotyped in 452 patients with breast cancer and 370 controls. Protein expression of NRF2 and SRXN1 was studied in 373 breast carcinomas by immunohistochemistry. Statistical significance of the associations between genotypes, protein expression, clinicopathologic variables, and survival was assessed. A high level (>25%) of cytoplasmic NRF2 positivity was observed in 237 of 361 (66%) and SRXN1 positivity was observed in 82 of 363 (23%) cases. The NRF2 rs6721961 genotype TT was associated with increased risk of breast cancer [P 1⁄4 0.008; OR, 4.656; confidence interval (CI), 1.350–16.063] and the T allele was associated with a low extent of NRF2 protein expression (P 1⁄4 0.0003; OR, 2.420; CI, 1.491–3.926) and negative SRXN1 expression (P 1⁄4 0.047; OR, 1.867; CI 1⁄4 1.002–3.478). The NRF2 rs2886162 allele A was associated with low NRF2 expression (P 1⁄4 0.011; OR, 1.988; CI, 1.162–3.400) and the AA genotype was associated with a worse survival (P1⁄4 0.032; HR, 1.687; CI, 1.047–2.748). TheNRF2 rs1962142 T allele was associated with a low level of cytoplasmic NRF2 expression (P1⁄4 0.036) and negative sulfiredoxin expression (P1⁄4 0.042). The NRF2 rs2706110 AA genotype was associated with an increased risk of breast cancer, and the SRXN1 rs6053666 C allele was associated with a decrease in breast cancer risk (P 1⁄4 0.011 and 0.017). NRF2 and SRXN1 genetic polymorphisms are associated with breast cancer risk and survival, implicating that mechanisms associated with reactive oxygen species and NRF2 pathway are involved in breast cancer initiation and progression. Cancer Res; 72(21); 5537–46. 2012 AACR.