The evaluation of large gastric folds poses a difficult diagnostic problem. Exploratory laparotomy with full-thickness gastric biopsy is frequently required in order to rule out malignancy. To examine the utility of endoscopic ultrasonography in the diagnostic evaluation of large gastric folds, 28 consecutive patients with endoscopically or radiographically diagnosed large gastric folds were studied; in most of these patients endoscopic biopsies had been inconclusive for malignancy. Sixteen subjects were women and 12 were men, with a mean age of 57 years (range, 23 to 84). All patients underwent endoscopic ultrasonography to determine the anatomic wall layer of enlargement; large-forceps biopsy with histopathologic review was then performed when appropriate. Endoscopic ultrasonography demonstrated enlargement of layer 2 only (deep mucosa) in 64% (18/28) of patients, primarily of layer 3 (submucosa) in 14% (4/28), and of layer 4 (muscularis propria) in 21% (6/28). Large-forceps endoscopic biopsy performed immediately after ultrasonography in 86% (24/28) revealed acute or chronic inflammation in 67% (16/24), malignancy in 16% (4/24), and Ménétrier's disease in 4% (1/24). The biopsy results of 3 patients (13%) were negative for malignancy, but because of ultrasonographic findings of wall thickening involving layers 3 and 4 (submucosa and muscularis propria), they underwent laparotomy, which revealed primary gastric adenocarcinoma. Endoscopic ultrasonography demonstrated gastric varices in 4 patients; biopsy specimens were not taken. One patient with gastric lymphoma had only a layer 2 abnormality, but the correct diagnosis was made by endoscopic biopsy. Malignancy did not develop in any of the patients with gastric wall thickening limited to layer 2 and negative biopsy results during a mean follow-up period of 35 months.(ABSTRACT TRUNCATED AT 250 WORDS)