Clear-cell renal cell carcinoma (ccRCC) may present with metastatic lesions in patients with a concurrent undiagnosed primary or a remote history of ccRCC. The thyroid is not uncommonly involved by metastatic ccRCC, in which a metastasis could be misinterpreted as a clear-cell change in adenomatoid nodules, follicular adenomas, or parathyroid glands. PAX8 is a transcription factor expressed by thyroid and renal-lineage cells. No previous study has evaluated the diagnostic use of PAX8 and ccRCC marker carbonic anhydrase IX (CAIX) in this setting. Cases of metastatic ccRCC in the thyroid (n=12), parathyroid glands and adenomas with clear-cell change (n=6), papillary thyroid carcinoma (n=6), thyroid follicular adenomas (n=5), and adenomatoid nodules with clear-cell change (n=5) were studied. Cases were assessed by standard immunohistochemistry for thyroid transcription factor-1 (TTF-1), thyroglobulin (TGB), PAX8, and CAIX. The extent and intensity of nuclear or cytoplasmic immunoexpression were assessed, with any labeling considered as a positive result. All metastatic ccRCCs were positive for PAX8 (moderate-to-strong, patchy-to-diffuse) and CAIX (strong, diffuse), and were negative for TTF-1 and TGB. All primary thyroid lesions labeled strongly and diffusely for TTF-1, TGB, and PAX8, and were negative for CAIX. Parathyroid tissues were negative for TTF-1, TGB, PAX8, and CAIX. An immunoprofile of "TTF1(-)/TGB(-)/CAIX(+) " was 100% sensitive and specific for metastatic ccRCC of the thyroid. The reverse profile "TTF1(+)/TGB(+)/CAIX(-)" supported a primary thyroid lesion. PAX8 was not useful in distinguishing metastatic ccRCC from thyroid lesions. Copyright © 2011 by Lippincott Williams & Wilkins.