Limited clinical data exist describing the use of direct-acting oral anticoagulants (DOACs) in patients with body mass index (BMI) >40 kg/m or body weight >120 kg. Thus, DOAC therapy in this population remains controversial. To investigate rivaroxaban as a safe and effective alternative to warfarin for venous thromboembolism (VTE) treatment and prevention of stroke in patients with atrial fibrillation identified as extremely obese or of high body weight. A retrospective chart review was performed at 2 academic medical centers in patients ≥18 years old and BMI >40 kg/m or weight >120 kg, newly initiated on warfarin or rivaroxaban for atrial fibrillation or VTE treatment. The primary end point was incidence of clinical failure, defined as VTE recurrence, stroke incidence, and mortality, within 12 months of initiation. Secondary end points included length of stay (LOS) and bleeding complications. A total of 176 patients were included, with 84 and 92 patients in the rivaroxaban and warfarin arms, respectively. Clinical failure was lower in the rivaroxaban group but did not reach statistical significance when compared with warfarin (5% vs 13%; = 0.06). LOS was significantly shorter in the rivaroxaban arm (2 days [1-3] vs 4 days [2-7], < 0.0001). Percentage of bleeding complications was higher in the rivaroxaban arm but not statistically significant (8% vs 2%, = 0.06). Although not statistically significant, rivaroxaban trended toward a lower incidence of clinical failure while demonstrating a significantly shorter LOS when compared with warfarin for VTE treatment or atrial fibrillation in morbidly obese or high-body-weight patients.