Thromboembolism is a serious complication of tamoxifen therapy in women with breast cancer. Banked DNA from tamoxifen-treated individuals with breast cancer from the Marshfield Clinic Personalized Medicine Research Project, a population-based DNA repository, was tested for association between incidence of tamoxifen-associated thromboembolic events (TTE) and single nucleotide polymorphisms encoding the estrogen receptors 1,2 (ESR1, ESR2) or drug metabolism enzymes cytochrome P450 2D6 (CYP2D6) and aromatase (CYP19). TTE were experienced by 16/220 subjects with risk association noted for XbaI (rs9340799) genotype and ESR1 Xbal/PvuII diplotype (rs9340799 and rs2234693) (hazard ratio 3.47, 95% CI 0.97-12.44, P = 0.035). Association persisted after adjusting for classical risk factors including age at diagnosis and body mass index at enrollment. Initial evidence of association between increased risk for TTE and ESR1 genotype and ESR1 diplotype is presented. Determination of estrogen receptor genotype may identify a subset of women at increased risk for thromboembolism with tamoxifen exposure.