The X-linked inhibitor of apoptosis (XIAP) is the most potent of the inhibitors of apoptosis, a group of related caspase inhibitors. X-linked inhibitor of apoptosis expression correlates with radio- and chemoresistance and clinical aggressiveness in certain tumors. XIAP expression was examined in 106 specimens from neoplastic and other thyroid disorders, which underwent citrate-based antigen retrieval and staining with monoclonal anti-XIAP. Normal thyroid was XIAP-negative. Of 35 papillary thyroid carcinomas (PTCs), 29 (83%) stained variably in intensity and/or extent. An insular carcinoma was strongly positive and 1 of 4 anaplastic carcinomas moderately positive. Follicular, medullary, and 3 of 4 anaplastic carcinomas, oncocytic neoplasms, and a hyalinizing trabecular tumor were nonstaining. Hashimoto's thyroiditis and adenomatous goiters were either nonstaining or occasionally stained in oncocytic foci. Because XIAP was highly specific for PTC among the thyroid neoplasms, it may be a useful marker for differential diagnosis when used alone or in combination with other markers. XIAP may also be useful in differentiating insular carcinoma from follicular neoplasm in certain difficult cases. In addition, the selective expression of XIAP in PTC and some high-grade thyroid malignancies also provides clues to the role of the apoptotic pathway in the tumorigenesis of these neoplasms.