Background: Obese individuals have been historically underrepresented in clinical trials. Considering their association with a higher risk of venous thromboembolism (VTE) and acute coronary syndrome (ACS), it is necessary to establish a more suitable anticoagulation regimen for this group of patients. Objectives: To evaluate the influence of obesity on the safety and efficacy of antithrombotic therapy in patients with ACS or VTE. Methods: This is a systematic review and meta-analysis that used 5 main international databases. We selected clinical trials or observational studies that compared the occurrence of clinical outcomes (mortality or bleeding) between obese and non-obese patients using parenteral anticoagulants for the treatment of ACS or VTE. P value < 0.05 was used for all analyses. Results: Six articles, with a total of 40,939 patients, were eligible, being 3 randomized clinical trials and 3 retrospective cohorts. Of the patients, 87.7% had ACS. The incidence of major bleeding was similar between groups (relative risk [RR]: 0.90, 95% confidence interval [CI]: 0.77 to 1.04, p = 0.14). The outcome remained comparable when studies were analyzed separately by anticoagulant: enoxaparin (RR: 0.87, 95% CI, 0.70 to 1.08, p = 0.21) or unfractionated heparin (RR: 0.96, 95% CI, 0.79 to 1.17, p = 0.67). The mortality rate was measured in only 2 studies, both in ACS, and it was lower in obese patients (RR: 0.71, 95% CI 0.59 to 0.87, p = 0.0007). Conclusion: In patients treated for VTE or ACS, rates of bleeding were comparable between obese and non-obese patients, regardless of the anticoagulant used. The lower mortality rate observed in obese patients may represent the effect of unaccounted confounding.