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Background: Hospital-associated venous thromboembolism is a major patient safety concern. Provision of prophylaxis to patients admitted for elective total knee replacement surgery has been proposed as an effective strategy to reduce the incidence of venous thromboembolism. We aimed to assess the relative efficacy and safety of all available prophylaxis strategies in this setting., Methods: We did a systematic review and Bayesian network meta-analyses of randomised controlled trials to assess the relative efficacy and safety of venous thromboembolism prophylaxis strategies and to populate an economic model that assessed the cost-effectiveness of these strategies and informed the updated National Institute for Health and Care Excellence (NICE) guideline recommendations for patients undergoing elective total knee replacement surgery. The Cochrane Library (CENTRAL), Embase, and Medline were last searched on June 19, 2017, with key terms relating to the population (venous thromboembolism and total knee replacement) and the interventions compared, including available pharmacological and mechanical interventions. Outcomes of interest were deep vein thrombosis (symptomatic and asymptomatic), pulmonary embolism, and major bleeding. Risk of bias was assessed, and relevant data extracted from the included randomised controlled trials for the network meta-analyses. Relative risks (RR; with 95% credible intervals [95% CrI]) compared to no prophylaxis, median ranks (with 95% CrI), and the probability of being the best intervention were calculated. The study was done in accordance with PRISMA guidelines., Findings: 25 randomised controlled trials were included in the network meta-analyses. 23 trials (19 interventions; n=15 028) were included in the deep vein thrombosis network, 12 in the pulmonary embolism network (13 interventions; n=15 555), and 19 in the major bleeding network (11 interventions; n=19 797). Risk of bias ranged from very low to high. Rivaroxaban ranked first for prevention of deep vein thrombosis (RR 0·12 [95% CrI 0·06-0·22]). Low molecular weight heparin (LMWH; standard prophylactic dose, 28-35 days) ranked first in the pulmonary embolism network (RR 0·02 [95% CrI 0·00-3·86]) and LMWH (low prophylactic dose, 10-14 days) ranked first in the major bleeding network (odds ratio 0·08 [95% CrI 0·00-1·76]), but the results for pulmonary embolism and major bleeding are highly uncertain., Interpretation: Single prophylaxis strategies are more effective in prevention of deep vein thrombosis in the elective total knee replacement population than combination strategies, with rivaroxaban being the most effective. The results of the pulmonary embolism and major bleeding meta-analyses are uncertain and no clear conclusion can be made other than what is biologically plausible (eg, that no prophylaxis and mechanical prophylaxis strategies should have the lowest risk of major bleeding)., Funding: National Institute for Health and Care Excellence., (Copyright © 2019 Elsevier Ltd. All rights reserved.)