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Paired box gene 8 (PAX8), a member of the thyroid-specific transcription factors, has recently been investigated as a useful marker of thyroid epithelial neoplasms. To the authors' knowledge, its utility in the immunohistochemistry of papillary thyroid carcinoma (PTC) has not been well studied to date. The goal of the current study was to compare the immunohistochemical expression of PAX8 with HBME-1 and cytokeratin 19 (CK19) expression on cell block preparations of PTC and benign thyroid nodules (BTN).Thirty-two cases of PTC and 20 cases of BTN diagnosed on fine-needle aspiration were included. The cell blocks were immunohistochemically stained for PAX8, HBME-1, and CK19.PAX8 demonstrated nuclear positivity in >90% of cases with PTC (31 of 32 cases; 96.9%) and BTN (20 of 20 cases; 100%), with a high sensitivity (0.97), but low specificity (0). HBME-1 and CK19 were found to have high sensitivity (0.78 and 0.75, respectively) and specificity (0.95 for both) for PTC. Statistically significant differences in staining intensity and distribution were noted for the PAX8 antibody (negative [1 of 32 cases] to weakly positive [20 of 32 cases] in 65.6% of PAX8-positive PTCs, and intermediate to strong in 100% of BTNs).In contrast to PAX8, HBME-1 and CK19 were found to have a high degree of both sensitivity and specificity for PTC. The results of the current study demonstrate that strong PAX8 staining appears to be typical of BTNs, whereas negative to weakly positive staining is noted in PTC. PAX8, HMBE-1 and CK19 may all play a role, particularly as a panel; however, the interpretation of PAX8 should consider the intensity and distribution of staining.