BACKGROUND: Cardiotoxicity is a well-recognised complication of chemotherapy with anthracycline and/or trastuzumab, and its prevention remains an important challenge in cancer survivorship. Several successful preventative strategies have been identified in animal trials. We sought to assemble the clinical evidence that prophylactic pharmacological interventions could prevent left ventricular (LV) dysfunction and heart failure in patients undergoing chemotherapy. METHODS: We undertook a systemic review of the evidence from randomised trials and observational studies where a prophylactic intervention was compared with a control arm in patients with a normal ejection fraction and no past history of heart failure. The primary outcome was development of heart failure (HF), a drop in ejection fraction (EF) or both. A random-effects model was used to combine relative risks (RR) and 95% confidence intervals (CIs), and a meta-regression was undertaken to assess the impact of potential covariates. FINDINGS: Data were collated from 14 published articles (n=2015 paediatric and adult patients) comprising 12 randomised controlled trials and two observational studies. The most studied chemotherapeutic agents were anthracyclines, and prophylactic agents included dexrazoxane, statins, beta-blocker and angiotensin antagonists. There were 304 cardiac events in the control arm compared to 83 in the prophylaxis arm (RR=0.31 [95% CI: 0.25-0.39], p<0.00001). Cardiac events were reduced with dexrazoxane (RR=0.35 [95% CI 0.27-0.45], p<0.00001), beta-blockade (RR=0.31 [95% CI 0.16-0.63], p=0.001), statin (RR=0.31 [95% CI 0.13-0.77], p=0.01) and angiotensin antagonists (RR=0.11 [95% CI 0.04-0.29], p<0.0001). INTERPRETATION: Prophylactic treatment with dexrazoxane, beta-blocker, statin or angiotensin antagonists appear to have similar efficacy for reducing cardiotoxicity.