Gastric lipoma is a rare tumor, accounting for only 5% of gastrointestinal tract lipomas and less than 1% of all gastric tumors. Histological diagnosis is usually easy. However, the tumor may sometimes undergo significant inflammatory changes leading to a difficult differential diagnosis with well-differentiated liposarcoma. Authors report the case of a 51-year-old man, presenting with epigastralgia of recent onset. Physical exam was unremarkable. Endoscopy revealed a large, ulcerated, submucosal, and antral tumor. CT scan showed an antral mass with fat attenuation. The patient underwent a total gastrectomy. Macroscopic examination identified in the antral wall a 9-cm, well-circumscribed, nodular lesion, with a greasy cut surface. On histological examination, the tumor was composed of a mature adipocytes proliferation, showing significant variation in cell size, associated to some lipoblasts. Nuclei were sometimes large, irregular, neither with hyperchromasia nor mitosis. Diagnosis of a well-differentiated liposarcoma was suspected and molecular cytogenetic analyses showed neither MDM2 nor CDK4 gene amplification on fluorescent in situ hybridization. The diagnosis of lipoma was made. Twelve months after surgery, the patient is doing well. In conclusion, Differentiating benign from malignant fatty tumors is sometimes difficult in morphologic features. In these cases, cytogenetic procedures are the only means for an accurate diagnosis.