Background Re-purposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with anti-viral and anti-inflammatory properties, has now been tested in numerous clinical trials.Areas of uncertainty We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemo-prophylaxis, among people with, or at high risk of, covid-19 infection. Data sourcesWe searched bibliographic databases up to April 25 2021. Two review authors sifted for studies, extracted data and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality.Twenty-four RCTs involving 3406 participants met review inclusion. Therapeutic Advances Meta-analysis of 15 trials found ivermectin reduced risk of death compared with no ivermectin (average Risk Ratio 0.38, 95% confidence interval (CI) 0.19 to 0.73; n=2438; I2=49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis (TSA) using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a TSA using the Biggerstaff-Tweedie method. Low-certainty evidence found ivermectin prophylaxis reduced covid-19 infection by an average 86% (95% CI 79% to 91%). Secondary outcomes provided less certain evidence. Low certainty evidence suggested that that there may be no benefit with ivermectin for ‘need for mechanical ventilation’, whereas effect estimates for ‘improvement’ and ‘deterioration’ clearly favoured ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.Conclusions Moderate-certainty evidence finds that large reductions in covid-19 deaths are possible using ivermectin. Employing ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.