Anticoagulation is an effective treatment in prevention of stroke in patients with atrial fibrillation (AF). Direct anticoagulants (DOACs) have been favored over vitamin K dependent antagonists (VKAs) given their safety and efficacy. However, there is limited real-world data on DOAC use among patients with extreme obesity. Describe the prescribing patterns of DOACs versus VKAs in patient with non-valvular AF (NVAF) and extreme obesity and the efficacy and safety of DOACs. Using a retrospective cohort study design, patients with NVAF, receiving oral anticoagulants (DOACs versus VKA), and extreme obesity (BMI ≥ 40 kg/m2 and/or weight ≥ 120 kg) during 2014 to 2020 at large healthcare system are included. Primary efficacy outcome is ischemic stroke and primary safety outcome is major bleeding. Sociodemographic and clinical characteristics were compared between DOAC and VKA groups using chi-square test for categorical variables and student’s t-test for continuous variables. Cox proportional hazards model is used to compare the primary efficacy and safety outcomes between the groups. Of the 6,930 patients, about two-third (63%) were prescribed DOACs. Patients receiving VKA were significantly older in age compared to DOAC group (66.1 (±10.2) vs 62.9 (±10.7); P=0.0321). There were no statistically significant differences in DOAC prescription by gender, race, and BMI. Even among patients with a BMI >=50, DOAC prescription rate was 61%. Across three categories of CHA2DS2VASc score (i.e., < 2, 2-4 and ≥ 5), the rate of DOAC prescription ranged from 80% to 65% and 52% respectively. Patients with higher CHA2DS2VASc score were significantly more likely to receive a VKA prescription than DOACs (P < 0.001). A third of this study patients were on concomitant antiplatelet agents with a trend towards DOACS prescribing pattern (59% vs 41%, 0.0361). In Cox regression, DOACs were associated with a significantly lower risk of ischemic stroke (hazard ratio [HR]: 0.52; 95% confidence interval [CI]: 0.42, 0.65) and major bleeding (HR: 0.55; 95% CI: 0.59, 0.90) compared to VKA. Despite lack of safety and efficacy data from clinical trials, in this extreme obese group of NVAF patients, DOACs were preferred over VKAs without an increase in stroke or major bleeding events.