Fifty consecutive patients with extrinsic or submucosal masses, gastric ulcers, or surgical anastomoses suspected of malignancy but with previously negative findings on conventional forceps biopsy or brush cytology underwent endoscopic ultrasonography followed by fine-needle aspiration cytology. Diagnostic cytology results were obtained in 37 of 50 (74%) patients. In 11 of the 13 patients with negative fine-needle aspirates, the endosonographic findings supported the final diagnosis as assessed by clinical follow-up or surgical pathology findings. In all patients, endosonography was useful for identifying the extent of the lesion and detailing regional anatomy to permit an assessment of the safest and most appropriate site for needle biopsy. The highest yield was found in evaluating tumors extrinsic to the gastrointestinal tract that were impinging on the lumen (14 of 15 or 93%). In 14 patients who underwent subsequent surgical therapy, the accuracy of fine-needle aspiration cytology was 86% (12 of 14). No complications occurred in any of the patients. EUS combined with fine-needle aspiration cytology appears to be useful in the evaluation of extrinsic or submucosal masses and suspicious appearing ulcerative lesions and surgical anastomoses of the gastrointestinal tract when conventional biopsy and brush cytology techniques have been unsuccessful.