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Acute portal vein thrombosis is a rare medical event usually seen in liver disease, but it can also occur due to any inherited or acquired procoagulable state that triggers venous occlusion. Hormonal therapies have been associated with an increased risk of prothrombotic states. This case report documents a portomesenteric venous thrombosis in a postmenopausal woman with testosterone implant for the treatment of hypoactive sexual desire and discusses the importance of identifying hypercoagulable risk factors before initiating hormone replacement therapy. We want to improve the awareness of an unusual medical complication associated with hormone replacement therapy and shed light on how testosterone implants could facilitate a thrombotic event related to other risk factors such as obesity and chronic hypoxic states, as well as the importance of differential diagnosis in the evaluation of postmenopausal women on testosterone replacement therapy presenting with acute abdominal pain.