Objective: To estimate differences in the efficacy and safety of rivaroxaban versus fondaparinux, warfarin and dabigatran in prevention of venous thromboembolism (VTE). Such differences may influence the cost-effectiveness of thromboprophylaxis following total hip replacement (THR) or total knee replacement (TKR). Methods: Three large, randomized controlled trials (RCTs; RECORD1–3) demonstrated relative risk reductions (RRRs) in VTE events with rivaroxaban against enoxaparin of 70–79% (p<0.001) following THR and 49% following TKR (p<0.001). However, the effect of rivaroxaban relative to alternative prophylaxes is also important, including those presently in development. A systematic literature review identified RCTs comparing enoxaparin with warfarin, fondaparinux or dabigatran in THR or TKR. Indirect comparisons of rivaroxaban to each were conducted, using enoxaparin as common comparator. Whenever the comparison included more than three studies, a meta-regression was performed. Results presented are RRRs from those analyses. Results: Rivaroxaban showed statistically significant reductions in the incidence of key endpoints. In THR, when compared with fondaparinux, rivaroxaban was associated with RRRs of 56% in total VTE (p=0.015) and 89% (p=0.015) in symptomatic VTE. When compared with dabigatran, RRRs with rivaroxaban were 86% (p=0.0018) in symptomatic VTE and 77% (p<0.001) in total VTE. Similarly, when compared with warfarin, the RRR in symptomatic VTE with rivaroxaban was 92% (p=0.003). In TKR, rivaroxaban produced 67% (p<0.001) and 66% (p<0.001) reductions in total VTE and deep vein thrombosis (DVT) respectively, versus warfarin, and 50% (p<0.001) reductions in total VTE and DVT versus dabigatran. No other statistically significant differences were found. Importantly for a new anticoagulant, there were no increases in major bleeding so safety endpoints are unlikely to influence cost-effectiveness. Conclusion: Rivaroxaban reduced the incidence of overall or symptomatic VTE events relative to alternative prophylaxes without increased major bleeding, reflecting a better clinical profile. These risk reductions may have implications for cost-effectiveness analyses.