Large gastric folds (LGF) can be caused by benign conditions as well as malignancies. Unfortunately, endoscopic features and biopsy results are often equivocal, making the diagnosis and management of large gastric folds difficult. Polyposis syndromes encompass a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gut. Large gastric folds are extremely rare in these syndromes. We present the case of a patient with polyposis who was found to have large gastric folds in the entire gastric fundus and body, mimicking malignancy. The patient's medical history and endoscopic ultrasonography (EUS) with mucosal resection confirmed the diagnosis of a pre-malignant disease. The lesion was monitored by serial endoscopic ultrasonography and biopsy, abdominal computed tomography (CT), and positron emission and computed tomography (PET-CT) for 6 years. The lesion remained stable, with the exception of abnormal fluorodeoxyglucose uptake on PET-CT in the gastric folds, which was determined to be a false-positive sign. To date, the patient remains healthy. We further discuss the mechanisms underlying the formation of large gastric folds caused by polyposis syndromes. Helicobacter pylori (H. pylori) or cytomegalovirus (CMV) is unnecessary for this progression. Immunohistochemistry (IHC) staining suggested that overexpression of transforming growth factor alpha (TGF-α) and down-regulation of myocyte enhancerbinding factor 2 (MEF2) may be involved in this case.