Objective: To detect the expression of special AT-rich sequence-binding protein 2 (SATB2) in neuroendocrine tumors and to explore its diagnostic value. Methods: The expression of SATB2 was detected using immunohistochemical EnVision two-step method in 153 neuroendocrine tumors. Results: SATB2 was strongly positive in 93.8% of rectal neuroendocrine tumors (30/32), but not in other digestive tract tumors (0/6 of esophagus, 0/16 of stomach, 0/6 of duodenum, 0/6 of pancreas and 0/8 of pancreas). In rectal neuroendocrine tumors, 31 patients had moderate to diffuse nuclear staining. In lung tissues, 20.0% (4/20) of small cell carcinomas were weakly positive, and 0 case of carcinoid were negative. In thyroid tissue, SATB2 was weakly positive in 5/38 (13.2%) of medullary carcinomas. In adrenal glands, SATB2 was positive in 0/9 (0%) pheochromocytoma and 0/15 (0%) cortical adenoma. SATB2 had high sensitivity and specificity in the diagnosis of rectal neuroendocrine tumors. In addition, SATB2 had good negative predictive value and positive predictive value in the differential diagnosis of rectal neuroendocrine tumors compared with digestive tract neuroendocrine tumors. Conclusion: SATB2 is a sensitive and specific marker for the diagnosis of rectal origin of neuroendocrine tumors.