Background Gastrointestinal (GI) neuroendocrine tumors are highly metastatic. Thioredoxin-Interacting Protein (TXNIP) is a metastasis suppressor gene that has been reported to be downregulated in metastatic neuroendocrine tumors such as pheochromocytomas. We hypothesized that TXNIP expression may also be reduced in metastatic GI neuroendocrine tumors. Methods Nine patients with GI neuroendocrine tumors were treated with surgical resection, and tumor tissue samples were collected for analysis. Clinical, operative, and pathology findings were reviewed. Tumor lysates were prepared and Western blot analysis using anti-TXNIP antibody was performed. TXNIP protein expression was quantified and correlated with clinical characteristics for each patient. Results For the patients with GI neuroendocrine tumors, the average age was 52±5 years, and 67% were female. The primary site of the neuroendocrine tumors included pancreas (5), small bowel (1), ampulla (1), appendix (1), and colon (1). Six patients (67%) had stage IV disease with distant metastases, two (22%) had stage III disease with nodal metastases, and one patient (11%) hade localized stage I disease. Of the patients with stage IV disease, four had liver metastases and two had carcinomatosis. Western analysis demonstrated TXNIP protein expression to be significantly reduced in GI neuroendocrine tumors with distant metastases (average TXNIP intensity 16 ± 3.9) compared to non-metastatic tumors (average TXNIP intensity 35 ± 7.1, p = 0.01, Wilcoxon signed rank test). Conclusions TXNIP expression is reduced in metastatic GI neuroendocrine tumors. Downregulation of this metastasis suppressor may be an important step in neuroendocrine tumor progression to a metastatic phenotype. Restoration or induction of TXNIP represents a potential therapeutic strategy for the prevention of metastases in patients with GI neuroendocrine malignancies.