Aromatase inhibitors (AIs) have been associated with cardiovascular disease in adjuvant randomized controlled trials (RCTs) comparing these drugs to tamoxifen. However, it is unclear whether this risk is real or due to cardioprotective effects of tamoxifen. To address this question, we conducted a systematic review and meta-analysis of all RCTs of AIs and tamoxifen in adjuvant and extended adjuvant setting. We searched PubMed, Embase (OVID), Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to June 2016 for all RCTs comparing cardiovascular and cerebrovascular safety of AIs to tamoxifen, AIs to placebo or no-treatment, or tamoxifen to placebo or no-treatment in the adjuvant or extended adjuvant setting. Relative risks (RRs) were pooled using DerSimonian and Laird random-effects models with analyses stratified by RCT design. A total of 19 RCTs were included in the meta-analysis (n  =  62 345). In the adjuvant setting, AIs were associated with a 19% (RR: 1.19, 95% confidence interval CI: 1.07–1.34) increased risk of cardiovascular events compared with tamoxifen. AIs were not associated with an increased risk compared with placebo in the extended-adjuvant setting (RR: 1.01, 95% CI: 0.85–1.20). In the adjuvant setting, tamoxifen was associated with a 33% (RR: 0.67, 95% CI: 0.45–0.98) decreased risk compared with placebo or no-treatment. The results from extended adjuvant RCTs comparing tamoxifen to placebo were inconclusive but suggestive of a small protective effect (RR: 0.91, 95% CI: 0.77–1.07). The increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter. This new evidence should be considered when assessing the benefits and risks of AIs in the treatment of breast cancer.