OBJECTIVES: The objective of this meta-analysis was to systematically review the randomized clinical trials (RCTs) of Fondaparinux sodium 2.5 mg once daily versus low molecular weight heparins (LMWH) at the titrated dose for the prophylaxis of venous thromboembolism (VTE) among the patients who are at risk as per Virchow’s triad. METHODS: Systematic search in the database e.g. EMBASE, MEDLINE, Cochrane Library, ProQuest, Science Direct, Google Scholar and clinicaltrials.gov was done to identify RCTs evaluating both treatments for the prophylaxis of VTE among patients at risk published in English language from the year 2000 to 2016. A web-based systematic review tool “Covidence” was used to systematically screen the studies of interest. Analysis in “RevMan” was performed with the relative odds based on the random effect model. Results were presented as odds ratios (OR) with their 95% confidence intervals. The assessment of study quality and risk of bias among the included studies was performed as per Cochrane collaboration. RESULTS: After screening 10, 506 articles, 4,676 were selected for review. Thirteen RCTs were included in the final analysis after reviewing these 4,676 articles. Pooled analyses showed a significant 54% reduction for VTE (OR=0.46 [0.36, 0.60]) and 11% reduction in mortality (OR=0.89 [0.63, 1.25]) with Fondaparinux compared to LMWH. Contrarily, there was a significant 47% increase in the risk for the major bleeding (OR=1.47 [1.14, 1.89]) and 16% increase in minor bleeding (OR=1.16 [0.90, 1.49]) with Fondaparinux compared to LMWH. Quality assessment results identified four studies with high risk in the “blinding of participants and personnel” domain. CONCLUSIONS: This meta analysis concluded that Fondaparinux showed a superior efficacy in terms of reduction of VTE and mortality. However, it also increased the risk for major bleeding. Thus, observation is warranted to prevent the adverse effects post Fondaparinux administration.