OBJECTIVES: : To compare the efficacy and safety of several different anticoagulant therapies in high-risk surgical patients using a mixed treatment comparison (MTC) approach.  METHODS: A manual literature search for randomised double blind controlled trials (RDBCTs) was undertaken that compared any two of the following agents: enoxaparin, rivaroxaban, unfractionated heparin (UFH) or placebo and reported rates of venous thromboembolism (VTE) in patients undergoing total hip replacement, hip fracture surgery, total knee replacement and general surgery. Bayesian methods of MTC meta-analysis were applied to synthesize data from 31 RDBCTs. Safety data (defined as major haemorrhage) were extracted when available. Patients received prophylaxis for up to 15 days, or extended therapy up to 35 days post-surgery. RESULTS: All treatments were compared to placebo using the Odds Ratio as a measure of efficacy. When compared to placebo, the incidence of VTE was reduced by ≥50% with prophylactic therapy post-hip surgery; patients undergoing extended prophylaxis with enoxaparin or rivaroxaban received the greatest benefit, with a reduction in the risk of VTE of 87% or 95% respectively.  Prophylaxis also reduced the incidence of VTE after knee surgery by ≥80%; patients treated with enoxaparin or rivaroxaban were 87% or 92% less likely to experience VTE, respectively, when compared to placebo.  Prophylaxis after general surgery significantly reduced the risk of VTE over placebo by ≥76%.  The risk of major haemorrhage was highest with UFH, followed by rivaroxaban and enoxaparin. CONCLUSIONS: The MTC approach resulted in a comprehensive examination of the effect of thromboprophylaxis on the rate of VTE and major haemorrhage in high-risk surgery.  Upon examining the body of clinical data, the evidence is clear: thromboprophylaxis is highly effective at preventing VTE in patients undergoing high-risk surgery.  When compared with rivaroxaban and UFH, prophylaxis with enoxaparin resulted in similar and lower incidence of VTE respectively, with less major haemorrhage.