Most pancreatic endocrine neoplasms (PENs) have distinctive endocrine growth patterns and uniform nuclear morphology; they are regarded as relatively low-grade tumors. Significant nuclear pleomorphism is a feature that may raise concerns about aggressive behavior or even obscure the endocrine nature of the neoplasm. Eight PENs exhibiting marked nuclear pleomorphism (>20% of the tumor cells) were identified during a review of 136 PENs (5.9%) from the pathology files of Memorial Sloan-Kettering Cancer Center. The histologic, immunohistochemical, ultrastructural (4 cases), and clinical features were reviewed. There were 6 males and 2 females ranging from 30 to 69 years (mean, 55 years). The tumors averaged 5.8 cm (range, 1.5-14 cm). Six tumors (75%) were initially misdiagnosed in 5 cases as adenocarcinoma and in one as solid-pseudopapillary tumor; in 2 cases, the misdiagnosis was based on fine needle aspiration cytology and in 4 on histologic examination. The architectural features of the tumors resembled those of other PENs, but the nuclei were markedly enlarged, irregularly shaped, and hyperchromatic, with frequent bizarre forms. Cells with pleomorphic nuclei also generally had abundant cytoplasm, sometimes with large perinuclear glassy inclusions. The mitotic rate was not elevated compared with other PENs, averaging 1.9 (range, 0-7) per 50 high power fields. Immunohistochemical findings were (number positive/number stained): chromogranin (8 of 8), synaptophysin (7 of 8), progesterone receptor (4 of 7), CD99 (2 of 5), S-100 protein (3 of 7), and p53 (0 of 6). Scattered cells expressed peptide hormones in a minority of cases. By electron microscopy, abundant dense core granules were identified, in some cases embedded within perinuclear arrays of intermediate filaments. Six patients underwent curative resection; at follow-up, 4 were free of disease at 11, 13, 30, 112 months (mean, 42 months), 1 developed liver metastases at 77 months and was alive with disease at 94 months, and 1 was lost to follow-up. Two patients had unresectable tumors and were alive with disease at 10 and 78 months. Striking nuclear pleomorphism may occur in otherwise typical PENs and commonly causes difficulties in the distinction from adenocarcinoma. There does not appear to be prognostic significance to these nuclear changes, and the morphologic features of pleomorphic PENs otherwise resemble those of their conventional counterparts.