The evidence regarding the risks, benefits, and quality of life impact of tamoxifen and raloxifene for prevention of breast cancer in postmenopausal women was reviewed. Five placebo-controlled trials were identified, four with tamoxifen and one with raloxifene. The individual placebo-controlled trials of tamoxifen for breast cancer prevention vary in size and risk status of the women who participated. An overview of the four trials found a 30% to 40% reduction in the risk of breast cancer. Serious adverse events include an increased risk of uterine cancer, venous thromboembolic events, and cataracts. Fracture risk was reduced. Quality of life was not significantly impaired, but women treated with tamoxifen had more vasomotor symptoms and vaginal discharge. In the single trial of raloxifene in postmenopausal women, there was a substantial reduction in the risks of breast cancer and fracture and no increased risk of uterine cancer. However, there was an increased risk of venous thromboembolic events. In the trial directly comparing tamoxifen with raloxifene in postmenopausal high-risk women, there was no significant difference in the risk of invasive breast cancer, but tamoxifen significantly reduced noninvasive breast cancer. The toxicity profiles for the two drugs were similar, with the exception of fewer hysterectomies, pulmonary emboli, and deep vein thrombosis in the raloxifene-treated group. There are now two effective Selective estrogen-receptor modulators available for use in postmenopausal women to reduce the risk of breast cancer. Women at high risk of breast cancer should be offered this therapy, and if one drug is not well tolerated, the other should be considered.