Gastrointestinal stromal tumors (GISTs) are rare but challenging tumors regarding the diagnosis and therapy. The symptomatology depends on the tumor size and location, and can be totally non-specific, as in the present case. We present the case of a 76-year-old female that was hospitalized with postprandial nausea and vomiting. Bulging of the posterior wall of the stomach was seen at endoscopically examination and confirmed by the computed tomography. Surgical resection of the 120×100 mm-sized tumor that involved the posterior gastric wall and gastrocolic ligament, was performed; the posterior wall of the stomach was also partially excised. Histological examination revealed a 120×95×70 mm nodular tumor with solid aspect and large necrotic and hemorrhagic area on cut section. The tumor cells were marked by c-KIT, DOG-1, smooth muscle actin and MSH-2 and were negative for Ki67, maspin, E-cadherin, S-100, and keratin AE1÷AE3. The resection margins were free of tumor cells. No recurrences were reported three years after surgical intervention; no postoperative chemotherapy was performed. This case highlights that a well-conducted trans-disciplinary approach can have real benefits, even in borderline-operable giant potentially-malignant GISTs. New criteria to establish the malignant potential of GIST should be explored.