The response to treatment for breast cancer is likely predicted by a number of disease and tumor tissue characteristics, many of which are under active investigation. One area that has received little attention is that of endogenous capabilities to respond to reactive oxygen species and subsequent byproducts resulting from radiation therapy and a number of chemotherapeutic agents, preventing cytotoxicity toward tumor cells. The glutathione S-transferases are key conjugating enzymes in this response, and GSTM1 and GSTT1 have deletion polymorphisms that result in no enzyme activity. In this retrospective study, we evaluated the role of GSTM1- and GSTT1-null genotypes on disease-free and overall survival among 251 women who received treatment for incident, primary breast cancer. Women were identified through Tumor Registry records and normal archived tissue retrieved for genotyping. Adjusting for age, race, and stage at diagnosis, women with null genotypes for GSTM1 and GSTT1 had reduced hazard of death [adjusted hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.36-0.97; and HR, 0.51; CI, 0.29-0.90, respectively] in relation to those with alleles present. Furthermore, women who were null for both GSTM1 and GSTT1 had one-third the hazard of death of those with alleles for both genes present (adjusted HR, 0.28; 95% CI, 0.11-0.70). Similar relationships were noted for risk of recurrence. These data indicate that interindividual differences in activity of enzymes that prevent therapy-generated reactive oxidant damage may have an important impact on disease recurrence and overall survival.