Purpose:Defective oxidative stress response may increase cancer susceptibility. In tumors, these rescue mechanisms may cause chemo- and radioresistance impacting patient outcome. We previously showed that genetic variation in the nuclear factor erythroid 2-related factor 2 (NFE2L2) is associated with breast cancer risk and prognosis. Here we further studied this pathway by investigating Kelch-like ECH-associated protein 1 (KEAP1). Experimental Design:Five tagging single nucleotide polymorphisms in the KEAP1 gene were genotyped in 996 breast cancer cases and 880 controls from two Finnish case-control sets. KEAP1 protein expression was studied in 373 invasive breast cancer tumors. Results:rs34197572 genotype TT was associated with increased risk of breast cancer in the KBCP samples (P=1.8x10-4, OR=7.314, CI=2.185-24.478). rs11085735 allele A was associated with lower KEAP1 protein expression (P=0.040, OR=3.545) and high nuclear NRF2 expression (P=0.009, OR=2.445), and worse survival in all invasive cases (P=0.023, HR=1.634). When including treatment data, rs11085735 was associated with recurrence-free survival (RFS) (P=0.020, HR=1.545) and breast cancer-specific survival (P=0.016,HR=1.683), and rs34197572 with overall survival (P=0.045, HR=1.304). rs11085735 associated with RFS also among tamoxifen-treated cases (P=0.003, HR=3.517). Among radiotherapy-treated cases, overall survival was associated with rs34197572 (P=0.018, HR=1.486) and rs8113472 (P=0.025, HR=1.455). RFS was associated with rs9676881 (P=0.024, HR=1.452) and rs1048290 (P=0.020, HR=1.468) among all invasive cases and among ER-positive tamoxifen-treated cases (P=0.018, HR=2.407, and 0.015, HR=2.476, respectively). Conclusions:The present findings suggest that the investigated SNPs have effects related to oxidative stress induced by cancer treatment, supporting involvement of the NRF2-KEAP1 pathway in breast cancer susceptibility and patient outcome.