Tamoxifen has been a mainstay of adjuvant therapy for breast cancer for many years. We sought to determine if genetic variability in the tamoxifen metabolic pathway influenced overall survival in breast cancer patients treated with tamoxifen. We examined functional polymorphisms in CYP2D6, the P450 catalyzing the formation of active tamoxifen metabolites, and UGT2B15, a Phase II enzyme facilitating the elimination of active metabolite in a retrospective study of breast cancer patients. We also examined whether the combination of variant alleles in SULT1A1 and UGT2B15 had more of an impact on overall survival in tamoxifen-treated patients than when the genes were examined separately. We conducted a retrospective study using archived paraffin blocks for DNA extraction and data from pathology reports and hospital tumor registry data for information on clinical characteristics, treatment, and outcomes (162 patients receiving tamoxifen and 175 who did not). Genotypes for CYP2D6 and UGT2B15 were obtained and Cox proportional hazards modeling was performed. After adjusting for age, race, stage of disease at diagnosis, and hormone receptor status, we found no significant association between CYP2D6 genotype and overall survival in either group of breast cancer patients. Tamoxifen-treated patients with UGT2B15 high activity genotypes had increased risk of recurrence and poorer survival. When UGT2B15 and SULT1A1 'at-risk' alleles were combined, women with two variant alleles had significantly greater risk of recurrence and poorer survival than those with common alleles. These studies indicate that genetic variation in Phase II conjugating enzymes can influence the efficacy of tamoxifen therapy for breast cancer.