The proximate cause of cancer cell death by radiation therapy and a number of therapeutic agents is through generation of reactive oxygen species, resulting in DNA damage as well as mitochondrial membrane disruption, triggering the apoptotic cascade. Because mitochondrial manganese superoxide dismutase catalyzes conversion of superoxide radicals to H2O2, with catalase neutralizing H2O2 and myeloperoxidase converting H2O2 to highly reactive hypochlorous acid, we hypothesized that gene variants could impact the efficacy of treatment for breast cancer and improve survival. Women who were treated with radiation and/or chemotherapy for incident breast cancer at the Arkansas Cancer Research Center from 1985 to 1996 were identified. DNA was extracted from paraffin-embedded normal tissue (n = 279), and MnSOD, CAT, and MPO genotypes were determined using mass spectrometry. Cox proportional hazards models were adjusted for age, race, stage with node status, and estrogen receptor and progesterone receptor status. Women who were homozygous for MPO G alleles, associated with increased transcription, had better survival (hazard ratio, 0.60; 95% confidence interval, 0.38-0.95; P = 0.03) than those with common alleles. Both CAT TT and MnSOD CC genotypes were associated with nonsignificant reduced hazard of death. When we combined genotypes associated with higher levels of reactive oxygen species for MnSOD and MPO, women with MnSOD CC and MPO GG genotypes had a 3-fold decrease in hazard of death (hazard ratio, 0.33; 95% confidence interval, 0.13-0.80; P = 0.01). These data indicate that gene variants that impact oxidative stress modify prognosis after treatment for breast cancer.