Giant gastric folds (or large gastric folds) are found in both benign and malignant diseases, and differential diagnosis with either upper gastrointestinal X-ray or endoscopy is difficult. Sometimes, even endoscopic biopsy cannot establish a definitive diagnosis. Recently, endoscopic ultrasonography (EUS) has been used to study giant gastric folds. We performed EUS in 25 patients with giant gastric folds that had been detected with upper gastrointestinal X-ray or endoscopy. The definitive diagnoses were confirmed by histopathology, other examinations, or long-term follow-up. The final diagnoses of these 25 patients were gastric varices in eight, gastric lymphangiectasis in one, gastritis in four, gastric carcinoma (scirrhous type) in six, and gastric lymphomas in six. All patients with gastric varices had anechoic tortuous varicose veins in the submucosal layer. EUS images of gastric lymphangiectasis were similar to those of gastric varices. EUS revealed regular gastric wall thickening of the second (mucosa) and third (submucosa) layers in all cases of gastritis. The fourth (muscularis propria) layer was intact in the only case of mucosa-associated lymphoid tissue lymphoma (MALToma), but not in the other five cases of gastric lymphoma. The second and third layers of this MALToma were irregular in thickness and heterogenous in echogenicity, different from the characteristic EUS findings in gastritis. The fourth layer was markedly thickened only in malignant conditions. Differentiation of gastric cancer from lymphoma with EUS was difficult because of overlapping EUS findings. In conclusion, EUS is indicated for the differential diagnosis of giant gastric folds. In addition, it avoids the risk associated with biopsy of gastric varices.