ObjectivesTo systematically review the efficacy and safety of direct oral anticoagulants (DOAC) on preventing venous thromboembolism (VTE) after major orthopedic surgery (MOS).MethodsThe Cochrane Library, PubMed, EMbase, CNKI, WanFang Data and CBM databases were electronically searched for randomized controlled trials (RCTs) on the efficacy and safety of DOAC on preventing VTE after MOS from inception to March 2019. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using RevMan 5.3 software.ResultsA total of 22 RCTs involving 41 244 patients were included. The results of meta-analysis showed that: the rate of symptomatic deep vein thrombosis (DVT) after MOS in rivaroxaban (Peto OR=0.54, 95%CI 0.35 to 0.82, P=0.004) and apixaban (Peto OR=0.49, 95%CI 0.26 to 0.92, P=0.03) were lower than enoxaparin. Additionally, the rate of symptomatic pulmonary embolism (PE) after MOS in rivaroxaban was lower than enoxaparin (Peto OR=0.53, 95%CI 0.29 to 0.96, P=0.04), however, in major bleeding after MOS rivaroxaban was significant higher than enoxaparin (Peto OR=1.98, 95%CI 1.30 to 3.01, P=0.001).ConclusionsCurrent evidence shows that rivaroxaban and apixaban is superior to enoxaparin on preventing symptomatic DVT after MOS. Rivaroxaban is superior to enoxaparin on preventing symptomatic PE, however, the risk of major bleeding is higher than enoxaparin. Due to limited quality and quantity of the included studies, more high quality studies are required to verify the above conclusions.