BACKGROUND: Radiotherapy (RT) is frequently associated with late cardiovascular (CV) complications. The mean cardiac dose from irradiation of a left-sided breast cancer is much higher than that for a right-sided breast cancer. However, data is limited on the long-term risks of RT on CV mortality. HYPOTHESIS: RT for breast cancer is associated with long term CV mortality and left sided RT carries a greater mortality than right sided RT. METHODS: We searched PubMed, Cochrane Central, Embase, EBSCO, Web of Science, and CINAHL databases from inception through December 2015. Studies reporting CV mortality with RT for left- vs right-sided breast cancers were included. The principal outcome of interest was CV mortality. We calculated summary risk ratio (RR) and 95% confidence intervals (CI) with the random-effects model. RESULTS: The analysis included 289 109 patients from 13 observational studies. Women who had received RT for left-sided breast cancer had a higher risk of CV death than those who received RT for a right-sided breast cancer (RR: 1.12, 95% CI: 1.07-1.18, P < 0.001; number needed to harm: 353). Difference in CV mortality between left- vs right-sided breast RT was more apparent after 15 years of follow-up (RR: 1.23, 95% CI: 1.08-1.41, P < 0.001; number needed to harm: 95). CONCLUSIONS: CV mortality from left-sided RT was significantly higher compared with right-sided RT for breast cancer and was more apparent after > /=15 years of follow-up.