Objective. To evaluate the effect of body weight (BW) on safety and efficacy of direct oral anticoagulants (DOACs). Methods. We performed a meta-analysis of randomized controlled trials (RCTs) comparing DOACs with vitamin K antagonists (VKA) in patients with venous thromboembolism (VTE). Efficacy (prevention of recurrent VTE or VTE-related death) and safety (occurrence of major or clinically relevant non-major bleeding) outcomes were stratified according to patients' BW (low, normal, and high). Results. Six RCTs with a total of 27,023 patients were included. DOACs showed a similar efficacy to VKA in patients with high BW, normal BW, and low BW (RR 0.98, 95% CI 0.72, 1.35; RR 0.91, 95% CI 0.75, 1.09; and RR 0.84, 95% CI 0.57, 1.24, respectively). Safety was comparable among DOACs and VKA in patients with high BW and low BW (RR 0.93, 95% CI 0.65, 1.32; and RR 0.80, 95% CI 0.54, 1.20), whereas DOACs were marginally safer than VKA in normal-BW subjects (RR 0.82, 95% CI 0.67, 1.00). However, the difference among DOACs and VKA in the rate of bleeding episodes appeared similar in the three BW groups. Conclusions. Results of our meta-analysis suggested that DOACs might be a safe and effective therapeutic option for the treatment of acute VTE even in the patients with extreme body weights. However, other studies with larger study populations are warranted to confirm our findings.