There is increasing evidence that androgens play a significant role in the development and progression of breast cancer. 5alpha-Reductase (SRD5A2) is an enzyme that is expressed in androgen-dependent tissues, and it catalyzes the reduction of testosterone to its more bioactive form, dihydrotestosterone, which then transactivates a number of genes. One of these genes encodes for prostate-specific antigen (PSA), a favorable prognostic factor in breast cancer. The 3' untranslated region of the SRD5A2 gene contains either no TA repeats [(TA)0] or 9 [(TA)9] or 18 [(TA)18] repeats. Variations in the length of these dinucleotide repeats have been reported to influence the enzymatic activity of SRD5A2. In this study, we determined the TA genotypes in DNA from 141 well-characterized breast tumors and in DNA from whole blood of 70 women without cancer. The presence of TA genotypes was then associated with tumor cytosolic PSA concentrations and with clinicopathological variables, including disease-free survival and overall survival. Three genotypes, (TA)0 homozygote, (TA)0/(TA)9 heterozygote, and (TA)9 homozygote, were identified. No (TA)18 alleles were detected in any of the two patient groups. A statistically significant association between high PSA concentrations and (TA)0/(TA)9 or (TA)9 genotypes was observed (P = 0.004). (TA)0/(TA)9 or (TA)9 genotypes were found less frequently in patients at stage III or IV disease. TA genotypes were not associated with other clinicopathological variables by contingency table analysis. Patients with (TA)0/(TA)9 or (TA)9 repeats, when compared to those with genotypes homozygous for the (TA)0 allele, showed a significant reduction in the risk for relapse (P = 0.043). Long-term studies are needed to investigate the relevance of this polymorphism to breast cancer susceptibility.