Background and Purpose-Obesity is a risk factor for all-cause and cardiovascular death but, despite this, an inverse relationship between overweight or obesity and a better cardiovascular prognosis in long-term follow-up studies has been observed; this phenomenon, described as obesity paradox, has also been found evident in atrial fibrillation cohorts. Methods-We performed a systematic review on the relationship between body mass index and major adverse outcomes in atrial fibrillation patients. Moreover, we provided a meta-analysis of non-vitamin K antagonist oral anticoagulants (NOACs) trials. Results-An obesity paradox was found for cardiovascular death and all-cause death in the subgroup analyses of randomized trial cohorts; however, observational studies fail to show this relationship. From the meta-analysis of NOAC trials, a significant obesity paradox was found, with both overweight and obese patients reporting a lower risk for stroke/systemic embolic event (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.66-0.84 and OR, 0.62; 95% CI, 0.54-0.70, respectively). For major bleeding, only obese patients were at lower risk compared with normal weight patients (OR, 0.84; 95% CI, 0.72-0.98). A significant treatment effect of NOACs was found in normal weight patients, both for stroke/systemic embolic event (OR, 0.66; 95% CI, 0.56-0.78) and for major bleeding (OR, 0.72; 95% CI, 0.54-0.95). Major bleeding risk was lower in overweight patients treated with NOACs (OR, 0.84; 95% CI, 0.71-1.00). Conclusions-There may be an obesity paradox in atrial fibrillation patients, particularly for all-cause and cardiovascular death outcomes. An obesity paradox was also evident for stroke/systemic embolic event outcome in NOAC trials, with a treatment effect favoring NOACs over warfarin for both efficacy and safety that was significant only for normal weight patients.