This study was conducted to evaluate the efficacy and safety of apixaban versus warfarin in morbidly obese patients. A total of 250 morbidly obese patients with a body mass index (BMI) higher than 40 kg/m 2 or a body weight higher than 120 kg who were on anticoagulation therapy with either apixaban or warfarin for over one month were included in the study. This retrospective cohort, multicenter study was executed using the medical records of 125 morbidly obese patients treated with apixaban, while patients on warfarin were selected using a systemic random sampling to match the sample size of the apixaban group. There was no significant difference between apixaban and warfarin in the development of thromboembolic events and major bleeding. However, incidences of minor bleeding significantly decreased in the apixaban group compared to patients treated with warfarin. This difference was overcome by controlling serum creatinine and nonsteroidal anti-inflammatory drugs (NSAIDs). In conclusion, apixaban efficacy and safety are nearly the same as that of warfarin in morbidly obese patients with a lower incidence of minor bleeding with apixaban. Controlling serum creatinine and NSAIDs use may improve warfarin safety and decrease its complications.