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Thyroid transcription factor-1 (TTF-1) is a member of the homeodomain transcription family expressed in epithelial cells of the thyroid and lung. Although nuclear TTF-1 is generally considered a specific marker for lung and thyroid neoplasms, it has been reported to be positive in other types of tumors including colorectal carcinoma (CRC). During metastatic adenocarcinoma workup for patients who had a history of CRC, we identified 4 positive TTF-1 cases using clone 8G7G3/1. Three of the 4 corresponding primary carcinomas were also positive for TTF-1. Therefore, we sought to retrospectively investigate the expression of TTF-1 in 100 CRC cases constructed in tissue microarray blocks and whole tissue sections of the 4 primary tumors corresponding to the 4 positive metastases. In tissue microarray cases, all cases had negative nuclear staining. Our results suggest that during immunohistochemical workup for adenocarcinoma, especially when the differential diagnosis includes the lung and CRC, TTF-1 results should be interpreted with caution as a small percentage of CRC expresses this marker. Positive nuclear TTF-1 in a metastatic carcinoma does not rule out CRC primary. Clinicopathologic correlation, tumor morphology, and a panel of immunohistochemical markers are essential to render the correct diagnosis.