The presence of "clear" or lipid-rich cells within pancreatic neuroendocrine tumors is thought to be pathognomonic of von Hippel-Lindau (VHL) disease, especially in the context of multiple tumors. However, we encountered the presence of lipid-rich cells in six of 16 patients (eight microadenomas/adenomas) who had multiple endocrine neoplasia type I (MEN I). Three of the lesions (two microadenomas and one adenoma) were composed entirely of lipid-rich cells while the remaining five lesions had a component of lipid-rich cells. All lesions containing lipid-rich cells were negative for α-inhibin, but positive for chromogranin and synaptophysin. In addition, four of the eight lesions were glucagon positive. None of the patients had clinical symptoms related to hormone production. We suggest that lipid-rich cells are not reflexly indicative of VHL, and that they may be encountered in a proportion of cases of MEN I either focally or constituting the entire neuroendocrine lesion.