There are several genes that code for enzymes, including various forms of superoxide dismutase and glutathione peroxidase, that protect the cell against oxidative damage that, in turn, can lead to carcinogenesis. There are a few common genetic polymorphisms in these genes that lead to altered proteins. Three that have been identified are SOD2 Val-9Ala, GPX1 Pro198Leu, and the GPX1 GCG repeat (three alleles with four, five, or six repeats). The SOD2 variant has been associated with increased breast cancer risk in two studies. The GPX1 variants have not been studied with respect to breast cancer, but Pro198Leu has been associated with lung cancer. We conducted a case-control study of these three polymorphisms in incident, invasive breast cancer in Caucasian women under 55. There were 399 cases and 372 controls genotyped, of whom 488 were premenopausal, 208 postmenopausal, and 75 of unknown menopausal status. We were unable to replicate the previously observed association with SOD2 Val-9Ala and also found no association between breast cancer and GPX1 Pro198Leu. However, the allele of GPX1 containing four GCG repeats was significantly associated with breast cancer risk in premenopausal women (odds ratio, 1.55; 95% confidence interval, 1.04-2.30 for carriers versus noncarriers). There is a significant trend of increasing risk with increasing number of alleles with four GCG repeats (P = 0.03). This variant has not previously been reported to be associated with breast cancer.