Solid-pseudopapillary neoplasm of the pancreas is a very rare tumor. It most commonly occurs in young women and has unique pathologic features. Previous immunohistochemical studies demonstrated that most solid-pseudopapillary neoplasms were immunoreactive with antibodies directed against vimentin and neuron-specific enolase. Recently, expression of CD10 and CD56 in this tumor has been reported. In this report, we expanded the demographic profile, highlighting 3 cases of solid-pseudopapillary neoplasm of the pancreas that presented in an elderly woman, a young man, and a young woman and further characterized them histologically and immunophenotypically. Grossly, all 3 tumors were well circumscribed and had a variable degree of cystic formation, necrosis, and hemorrhage. Microscopically, these tumors were characterized by a pseudopapillary pattern of epithelioid cells arranged around a delicate fibrovascular core with sheets of bland epithelioid cells filling cystic spaces. Hyaline globules, cholesterol granulomas, and foamy cells were all seen to be common findings. Although these 3 tumors were strongly immunoreactive for vimentin, α-1-antitrypsin, α-1-antichymotrypsin, neuron-specific enolase, CD10, CD56, and progesterone receptor, they demonstrated only variable "positivity" for epithelial membrane antigen and broad-spectrum cytokeratin, but were being consistently nonreactive for synaptophysin, insulin, glucogon, chromogranin A, and estrogen receptor. Interestingly, 2 of the 3 tumors were S-100 protein and melanin A reactive but were nonreactive for HMB45. © 2006 Lippincott Williams & Wilkins, Inc.