Objective To investigate the safety and risk factors of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for pancreatic lesions. Methods Five thousand one hundred and sixty patients who underwent EUS-FNA in the Department of Endoscopy, Fudan University Shanghai Cancer Center from January 2012 to December 2022 were retrospectively reviewed. The incidence of adverse events was calculated, and independent risk factors were analyzed by univariate and logistic regression. Results The incidences of postoperative pancreatitis, intraoperative bleeding and postoperative bleeding were 1.38% (68/4 930), 0.82% (42/5 143) and 0.78% (40/5 143) respectively. No perforation or death occurred. Age >60 years (OR=0.581, 95%CI: 0.356-0.946, P=0.029), tumor located in the neck, body and tail (OR=0.355, 95%CI: 0.194-0.652, P=0.001), lesion diameter of >20-40 mm (OR=0.450, 95%CI: 0.227-0.893, P=0.023), and lesion diameter >40 mm (OR=0.382, 95%CI: 0.168-0.869, P=0.022) were independent protective factors for postoperative pancreatitis. Transduodenal puncture (OR=2.435, 95%CI: 1.319-4.496, P=0.005) was an independent risk factor for postoperative pancreatitis. Puncture for 3-4 pass (OR=0.439,95%CI: 0.235-0.821, P=0.010), lesion diameter of >20-40 mm (OR=0.154, 95%CI: 0.069-0.341, P<0.001), and lesion diameter >40 mm (OR=0.326, 95%CI: 0.143‑0.743, P=0.008) were independent protective factors for intraoperative bleeding. Fine‑needle biopsy (FNB) needle (OR=2.314, 95%CI: 1.189‑4.502, P=0.014) was an independent risk factor for postoperative bleeding. Conclusion EUS-FNA is a safe procedure with low incidence of adverse events. The occurrence of postoperative pancreatitis and intraoperative bleeding is mainly related to clinical characteristics of the lesion, while postoperative bleeding is related to the type of puncture needle.