Thirty-eight consecutive patients underwent endoscopic ultrasound-guided fine-needle aspiration. Of 46 lesions, 34 were extraluminal (12 pancreatic masses, 8 periesophageal nodes, 6 celiac nodes, 2 pericolonic masses, 1 mediastinal mass, 1 perigastric mass, 1 liver, 1 periduodenal node, 1 perirectal mass, 1 perirectal node) and 12 were submucosal (8 gastric, 3 duodenal, 1 esophageal). One hundred sixty-three passes were made, with an average of 3.5 passes per lesion and 4.3 passes per patient (range, 1 to 8). Adequate specimens were obtained from 91% of targeted lesions. The overall diagnostic accuracy was 87%. In patients with malignant lesions, sensitivity was 91% and specificity 100%. Celiac nodes were successfully sampled and diagnostic in 5 of 6 (83%) patients. No complications occurred. Using this technique, an initial tissue diagnosis of malignancy was made in 66% of cancer patients without a previous diagnosis and the preoperative stage was changed in 44% of cancer patients. The additional information gained by this modality directly influenced the decision not to perform surgery in 26% of patients with a primary malignancy. Endoscopic ultrasound-guided fine-needle aspiration is feasible and can be safely used to evaluate submucosal and extraluminal lesions in both the upper and lower gastrointestinal tract with a high degree of diagnostic accuracy.