Background Breast cancer is the most frequently occurring malignancy and the second cause of death for cancer in women. Cancer prevention agents (CPAs) are a promising approach to reduce the burden of breast cancer. Currently, two main types of CPAs are available: selective estrogen receptor modulators (SERMs, such as tamoxifen and raloxifene) and aromatase inhibitors (AIs, such as exemestane and anastrozole). Objectives To assess the efficacy and acceptability of single CPAs for the prevention of primary breast cancer, in unaffected women, at an above-average risk of developing breast cancer. Using a network meta-analysis, to rank single CPAs, based on their efficacy and acceptability (an endpoint that is defined as the inverse of CPA-related toxicity). Search methods We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MED-LINE, Embase, World Health Organization’s International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 17 August 2018. We handsearched reference lists to identify additional relevant studies. Selection criteria We included randomized controlled trials (RCTs) that enrolled women without a personal history of breast cancer but with an above-average risk of developing a tumor. Women had to be treated with a CPA and followed up to record the occurrence of breast cancer and adverse events. Data collection and analysis Two review authors independently extracted data and conducted risk of bias assessments of the included studies, and assessed the certainty of the evidence using GRADE. Outcome data included incidence of breast carcinoma (both invasive and in situ carcinoma) and adverse events (both overall and severe toxicity). We performed a conventional meta-analysis (for direct comparisons of a single CPA with placebo or a different CPA) and network meta-analysis (for indirect comparisons). Main results We included six studies enrolling 50,927 women randomized to receive one CPA (SERMs: tamoxifen or raloxifene, or AIs: exemestane or anastrozole) or placebo. Three studies compared tamoxifen and placebo, two studies compared AIs (exemestane or anastrozole) versus placebo, and one study compared tamoxifen versus raloxifene. The risk of bias was low for all RCTs. For the tamoxifen versus placebo comparison, tamoxifen likely resulted in a lower risk of developing breast cancer compared to placebo (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.62 to 0.76; 3 studies, 22,832 women; moderate-certainty evidence). In terms of adverse events, tamoxifen likely increased the risk of severe toxicity compared to placebo (RR 1.28, 95% CI 1.12 to 1.47; 2 studies, 20,361 women; moderate-certainty evidence). In particular, women randomized to receive tamoxifen experienced a higher incidence of both endometrial carcinoma (RR 2.26, 95% CI 1.52 to 3.38; high-certainty evidence) and thromboembolism (RR 2.10, 95% CI 1.14 to 3.89; high-certainty evidence) compared to women who received placebo. For the AIs versus placebo comparison, AIs (exemestane or anastrozole) reduced the risk of breast cancer by 53% (RR 0.47, 95% CI 0.35 to 0.63; 2 studies, 8424 women; high-certainty evidence). In terms of adverse events, AIs increased the risk of severe toxicity by 18% (RR 1.18, 95% CI 1.09 to 1.28; 2 studies, 8352 women; high-certainty evidence). These differences were sustained especially by endocrine (e.g. hot flashes), gastrointestinal (e.g. diarrhea), and musculoskeletal (e.g. arthralgia) adverse events, while there were no differences in endometrial cancer or thromboembolism rates between AIs and placebo. For the tamoxifen versus raloxifene comparison, raloxifene probably performed worse than tamoxifen in terms of breast cancer incidence reduction (RR 1.25, 95% CI 1.09 to 1.43; 1 study, 19,490 women; moderate-certainty evidence), but its use was associated with lower toxicity rates (RR 0.87, 95% CI 0.80 to 0.95; 1 study, 19,490 women; moderate-certainty evidence), particularly relating to incidence of endometrial cancer and thromboembolism. An indirect comparison of treatment effects allowed us to compare the SERMs and AIs in this review. In terms of efficacy, AIs (exemestane or anastrozole) may have reduced breast cancer incidence slightly compared to tamoxifen (RR 0.67, 95% CI 0.46 to 0.98; 5 RCTs, 31,256 women); however, the certainty of evidence was low. A lack of model convergence did not allow us to analyze toxicity data. Authors’ conclusions For women with an above-average risk of developing breast cancer, CPAs can reduce the incidence of this disease. AIs appear to be more effective than SERMs (tamoxifen) in reducing the risk of developing breast cancer. AIs are not associated with an increased risk of endometrial cancer and thromboembolic events. However, long-term data on toxicities from tamoxifen are available while the follow-up toxicity data on unaffected women taking AIs is relatively short. Additional data from direct comparisons are needed to fully address the issues of breast cancer prevention by risk-reducing medications, with special regards to acceptability (i.e. the benefit/harm ratio).