Background: Trials demonstrate the efficacy of medications to reduce the risk for invasive breast cancer. Purpose: To summarize benefits and harms of tamoxifen citrate, raloxifene, and tibolone to reduce the risk for primary breast cancer. Data Sources: MEDLINE and Cochrane databases from inception to January 2009, Web of Science, trial registries, and manufacturer information. Study Selection: Predefined eligibility criteria were used to select articles. English-language reports of randomized, controlled trials (RCTs) for benefits and RCTs and observational studies for harms were included. Data Extraction: Two reviewers assessed study data, quality, and applicability. Data Synthesis: Seven placebo-controlled RCTs and 1 head-to-head trial provide results for main outcomes. Tamoxifen (risk ratio, 0.70 [95% CI, 0.59 to 0.82]; 4 trials), raloxifene (risk ratio, 0.44 [CI, 0.27 to 0.71]; 2 trials), and tibolone (risk ratio, 0.32 [CI, 0.13 to 0.80]; 1 trial) reduce risk for invasive breast cancer compared with placebo by 7 to 10 per 1000 women per year. Tamoxifen and raloxifene reduce estrogen receptor–positive breast cancer but not estrogen receptor–negative breast cancer, noninvasive breast cancer, or mortality. All medications reduce fractures. Tamoxifen (risk ratio, 1.93 [CI, 1.41 to 2.64]; 4 trials) and raloxifene (risk ratio, 1.60 [CI, 1.15 to 2.23]; 2 trials) increase thromboembolic events by 4 to 7 per 1000 women per year; raloxifene causes fewer events than tamoxifen. Tamoxifen increases risk for endometrial cancer (risk ratio, 2.13 [CI, 1.36 to 3.32]; 3 trials) compared with placebo by 4 per 1000 women per year and causes cataracts compared with raloxifene. Tibolone causes strokes in older women. Limitations: Bias, trial heterogeneity, and a dearth of head-to-head trials limit this review. Data are lacking on doses, duration, and timing of the medications; long-term effects; and nonwhite and premenopausal women. Conclusion: Three medications reduce risk for primary breast cancer but increase risk for thromboembolic events (tamoxifen, raloxifene), endometrial cancer (tamoxifen), or stroke (tibolone). Primary Funding Source: Agency for Healthcare Research and Quality.