BACKGROUND Circulating epithelioid cells (CECs), also known as circulating tumor, circulating cancer, circulating epithelial, or circulating nonhematologic cells, are a prognostic factor in various malignancies that can be isolated via various protocols. In the current study, the authors analyzed the cytomorphologic characteristics of CECs isolated by size in a cohort of patients with benign and malignant pancreatic diseases to determine whether cytomorphological features could predict CEC origin. METHODS Blood samples were collected from 9 healthy controls and 171 patients with pancreatic disease who were presenting for surgical evaluation before treatment. Blood was processed with the ScreenCell size‐based filtration device. Evaluable CECs were analyzed in a blinded fashion for cytomorphologic characteristics, including cellularity; nucleoli; nuclear size, irregularity, variability, and hyperchromasia; and nuclear‐to‐cytoplasmic ratio. Statistical differences between variables were analyzed via the Fisher exact test. RESULTS No CECs were identified among the 9 normal healthy controls. Of the 115 patients with CECs (positive or suspicious for), 25 had nonmalignant disease and 90 had malignancy. There were no significant differences in any of the cytologic criteria noted between groups divided by benign versus malignant, neoplastic versus nonneoplastic, or pancreatic ductal adenocarcinoma versus neuroendocrine tumor. CONCLUSIONS CECs were observed in patients with malignant and nonmalignant pancreatic disease, but not in healthy controls. There were no morphologic differences observed between cells from different pancreatic diseases, suggesting that numerous conditions may be associated with CECs in the circulation and that care must be taken not to overinterpret cells identified by cytomorphology as indicative of circulating tumor cells of pancreatic cancer. Additional studies are required to determine the origin and clinical significance of these cells. Cancer Cytopathol 2017;125:332–340. © 2017 American Cancer Society. In the current study, circulating epithelioid cells (CECs) are isolated from blood in patients with both benign and malignant pancreatic disease at similar rates, but not isolated from healthy controls. These CECs appear to demonstrate no significant morphological differences between benign and malignant or between neoplastic and nonneoplastic diseases.