Background: EUS-guided FNA is effective for establishing tissue diagnosis in suspected pancreatic cancer. However, data on the frequency of major complications following EUS-FNA are limited. Objective: To evaluate the frequency of major complications after EUS-FNA of solid pancreatic masses. Design: Prospective cohort study. Setting: Tertiary University based referral center for pancreatico-biliary disorder. Patients: Consecutive patients who underwent EUS-FNA of a solid pancreatic over a 42-month period. All immediate complications were recorded by the endosonographer. Late complications were assessed at 72 hours and at 30-days after the procedure. Main Outcomes Measurements: Major complications were defined as acute pancreatitis, bleeding, infection, perforation, use of reversal medication, hospitalization or death. Results: A total of 355 consecutive patients with a solid pancreatic mass underwent EUS FNA. Major complications were encountered in 9 patients (2.54%, 95% CI 1.17-4.76). Acute pancreatitis occurred in 3 of 355 (0.85 %, 95% CI 0.17-2.45); 2 patients were hospitalized, and 1 patient recovered with outpatient analgesics. Three patients were admitted for severe pain after the procedure; all were treated with analgesics and subsequently discharged with no sequela. Two patients (0.56%, 95% CI 0.07-2.02) developed fever and were admitted for intravenous antibiotics; 1 patient recovered with intravenous antibiotics and the other required surgical debridement for necrosis. One patient required the use of reversal medication. Overall, 1.97% (95% CI 0.80-4.02) of the patients were hospitalized for complications (range 1-16 days). None of the patients experienced clinically significant hemorrhage, perforation, or death. No clear predisposing risk factors were identified. Limitations: Lack of surgical gold standard and referral to a tertiary center. Conclusions: EUS-FNA of solid pancreatic masses infrequently leads to major complications. Our results can be used by endosonographers to counsel patients before EUS-FNA of solid pancreatic masses. Copyright © 2006 by the American Society for Gastrointestinal Endoscopy.