The cytologic findings of a clear-cell pancreatic endocrine neoplasm (PEN) diagnosed by endoscopic ultrasound-guided fineneedle aspiration (EUS-FNA) occurring in a 29-year-old man with von Hippel-Lindau (VHL) syndrome are described. Imaging studies showed multiple pancreatic masses and cysts, a single liver lesion, and pulmonary and renal cysts. Cytologic features of this clear-cell PEN included the presence of large sheets and rounded clusters of polygonal neoplastic cells with relatively abundant cytoplasm containing numerous, small, sharply-demarcated vacuoles that occasionally indented nuclei and gave the cells a "frothy" appearance. Mild anisonucleosis was present and nucleoli were visible. Rare single cells and stripped nuclei were seen. Small vessels transgressed tumor cell sheets. These cytologic findings are distinct from those of typical endocrine neoplasms, and bear resemblance to the cytologic features of renal cell carcinoma metastatic to the pancreas. To the best of our knowledge, this is the first detailed report of the EUS-FNA cytologic findings of a clear-cell PEN associated with VHL syndrome. We believe that the distinctive and characteristic cytologic features, together with immunohistochemical studies, can allow a preoperative cytologic diagnosis of this highly unusual pancreatic lesion and avoid possible confusion with other clear-cell neoplasms in the pancreas, particularly metastatic renal cell carcinoma. © 2009 Wiley-Liss, Inc.