Twenty cases of papillary cystic tumor of the pancreas were studied (19 female patients, one male patient; median age, 19.5 years). Most tumors developed in the head or body of the pancreas as well-circumscribed, large masses. Gross examination showed that they were solid, cystic, and hemorrhagic. Preoperative fine-needle aspiration biopsy anticipated the diagnosis in four cases. Histologic examination showed that uniform cells formed solid sheets, and loss of cohesion produced pseudopapillae. Hemorrhage, foam cells, cholesterol granulomas, and entrapped nests of pancreatic parenchyma were often found. Fifteen cases studied immunohistochemically were reactive for vimentin and alpha-1-antitrypsin, 13 expressed neuron-specific enolase, 2 expressed cytokeratin, and 1 expressed S-100 protein. None were reactive for pancreatic hormones, opioid peptides, hormonal receptors, or neuroendocrine markers. Electron microscopic examination in five cases showed oval nuclei, moderate amounts of rough endoplasmic reticulum, and many mitochondria; it also showed that annulate lamellae were common. No diagnostic secretory granules were found. DNA study in nine cases revealed a diploid GO/1 peak in eight and hyperdiploid (diploid index = 1.1) DNA content in one case. Fourteen patients with follow-up were free of disease (mean, 2.6 years). Papillary cystic tumor of the pancreas possibly originates from primordial pancreatic cells and lacks definite evidence of endocrine or exocrine differentiation.