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Introduction: Duodenal leiomyoma is a rare tumor, originating in the intestinal wall smooth muscle, making up <0.1% of all gastrointestinal tumors. The majority are discovered incidentally on endoscopy due to the small size of tumors at presentation. Larger duodenal leiomyomas may present with anemia from gastrointestinal hemorrhage. Case presentation: A 67-year-old male presented with life-threatening upper gastrointestinal hemorrhage. Magnetic resonance imaging identified an 11.9 × 8.7 cm submucosal mass in the second portion of the duodenum adjacent to the pancreatic head. An urgent upper endoscopy confirmed active hemorrhage, which was controlled with endoscopic clips. The patient underwent a successful resection of the tumor with no postoperative complications. Discussion: The diagnosis of duodenal leiomyomas remains challenging due to the lack of symptom manifestations. The differential diagnosis for a duodenal soft tissue mass includes gastrointestinal stromal tumor, solitary fibrous tumors, schwannoma, lymphoma, duodenal adenocarcinoma, and leiomyosarcoma. Radiographically, leiomyomas have typical imaging characteristics similar to skeletal muscle with marked T2 hypointensity, gradual enhancement on post contrast images, and the absence of extensive lesional necrosis. Surgical resection allows pathological confirmation of tissue diagnosis. Histopathologically, leiomyoma exhibits bland smooth muscle cells, with a low Ki67 proliferative index and absence of mitotic figures. Leiomyoma immunohistochemistry profile is positive for smooth muscle antigen and desmin. Conclusion: Reported is the largest case of an 11.9 cm giant duodenal leiomyoma with life-threatening gastrointestinal hemorrhage, providing the first comprehensive radiological-histopathological correlation for a giant duodenal leiomyoma. Surgical resection remains the primary treatment to confirm the pathological diagnosis of benign leiomyoma and manage symptoms.