Histomorphologic features and routine endocrine immunohistochemical (IHC) markers do not differentiate neuroendocrine tumors (NETs) in relation to their location, making it difficult to establish the site of origin of a metastatic neoplasm. Site-specific markers would be useful, particularly when examining small biopsies. CDX-2 and thyroid transcription factor-1 (TTF-1) are transcription factors that have been recently proposed as IHC markers of intestinal and pulmonary adenocarcinomas, respectively. However, their expression in NETs has not been widely studied. The objective of this study is to evaluate the expression of TTF-1 and CDX-2 in NETs and their potential usefulness in distinguishing gastrointestinal and pulmonary NETs from other sites. We performed an IHC study on formalin-fixed, paraffin-embedded sections from 155 primary NETs, including 60 pulmonary, 60 gastrointestinal, 30 pancreatic, and 5 NETs from other sites. In addition, we evaluated 13 metastatic NETs, including 11 cases of gastrointestinal and 2 of pulmonary origin. In this study, CDX-2 was expressed in 28/60 (47%) of gastrointestinal NETs with the following results: 11/11 (100%) appendiceal, 12/14 (86%) small intestinal, 3/4 (75%) colonic, 2/11 (18%) rectal, and 0/20 (0%) gastric. TTF-1 was expressed in pulmonary carcinoid tumors in 13/30 (43%) and in 27/30 (90%) pulmonary small cell carcinomas. NETs of other origins (pancreas, skin, ovary, and thymus) were negative for both TTF-1 and CDX-2. Metastatic neuroendocrine neoplasms of intestinal origin were positive for CDX-2 and negative for TTF-1. In conclusion, CDX-2 expression is highly specific in identifying NETs of intestinal origin and TTF-1 expression is helpful in identifying NETs of pulmonary origin, which can be quite useful in the diagnosis of metastatic NETs of unknown origin.