Rectal neuroendocrine tumors (NETs) can be classified by histologic pattern and secretory products. Recently, rectal NETs have been noted to exhibit immunohistochemical (IHC) positivity for Islet 1 and PAX8, which are generally considered markers for NETs of pancreatic origin. In this study, we sought to characterize the IHC staining profile of rectal NETs and determine whether there was any correlation between the histologic pattern of rectal NETs and their IHC profile. Fifty-six primary rectal NETs were histologically reviewed and stained with antibodies against Islet 1, PAX8, CDX2, chromogranin A, and synaptophysin. In a subset of 31 cases, immunoreactivity for serotonin, pancreatic polypeptide (PP), and prostatic acid phosphatase (PAP) was also studied. By morphology, the tumors studied included 55 % trabecular, 27 % solid nested, 4 % acinar, and 14 % mixed patterns. Islet 1 was positive in 89 % and PAX8 in 79 % of cases. CDX2 was negative in all 56 cases. Cytoplasmic staining was observed for chromogranin A in 30 % of cases and for synaptophysin in all 56 cases. Cytoplasmic staining for serotonin, PP, and PAP was present in 16, 61, and 97 % of cases, respectively. There was no correlation between histologic pattern and IHC staining pattern with any of the antibodies studied. We have demonstrated that Islet 1 and PAX8 are not entirely specific for NETs of pancreatic origin, as they are expressed in a majority of rectal NETs. Since rectal NETs may show an IHC staining profile which mirrors that of pancreatic NETs (Islet 1 and PAX8-positive, CDX2-negative), a metastatic rectal NET should be considered in the differential diagnosis and ruled out clinically in the work-up of a metastatic NET of unknown primary origin which exhibits this staining profile. © 2013 Springer Science+Business Media New York.