Three cases of clinically benign pancreatic papillary cystic tumors in young female patients were studied by immunohistochemistry and electron microscopy in order to define the cellular nature of this type of neoplasm. Two of the tumors showed focal cytokeratin- and desmoplakin-positivity as evidence of focal epithelial differentiation, while the tumor cells were in all cases positive for vimentin--the intermediate filament protein typical of (but not specific for) mesenchymal cells. Electron microscopy showed some cell-cell junctions, but there was no evidence of acinar or islet cell differentiation. The tumors were at least focally positive for neuron-specific enolase, and small clusters of polypeptide hormone immunoreactive cells were present in all cases (glucagon 3/3, somatostatin 2/3, insulin 2/3). However, the tumors were negative for synaptophysin and neurofilament proteins, unlike most islet cell tumors. Trypsin and chymotrypsin immunoreactivity was found in all tumors, but because many nonpancreatic carcinomas were also positive, we doubt whether these two enzyme proteins can act as specific markers for pancreatic acinar cell differentiation. Two of the tumors that were studied immunohistochemically for the presence of nuclear estrogen receptors, were negative. Therefore no proof of the suggested hormone dependence of this tumor could be obtained. We conclude that papillary cystic tumor is a neoplasm of primitive pancreatic epithelial cells, that may exhibit focal endocrine cell differentiation.