AbstractThe cytologic diagnosis of papillary thyroid carcinoma is straightforward in most instances. However, there are some mimics including goitrous nodules and Hurthle cell neoplasms. Many studies have shown the combination of HBME‐1 and CK19 expression to be useful in reaching a correct histologic diagnosis on tissue sections. We aim to assess the value of these markers in the setting of cell blocks prepared from needle aspiration specimens. We performed immunohistochemical staining of HBME‐1 and CK19 on cell block material from 22 thyroid nodules that also had follow‐up histology. Both CK19 and HBME‐1 were strongly positive in all nine cases of papillary thyroid carcinoma, the latter showing distinct luminal accentuation. In the non‐papillary carcinomas, none showed positivity for both HBME‐1 and CK19. Two of six Hurthle cell neoplasms were positive for CK19, however all were negative for HBME‐1. One of nine goitrous nodules was strongly positive for HBME‐1 with luminal/membranous staining, but this were negative for CK19.The sensitivity, specificity and positive predictive value of HBME‐1 in distinguishing between papillary thyroid carcinoma and goitrous nodules/Hurthle cell neoplasms were found to be 100%, 92.9% and 0.9, respectively; and that of HBME‐1 and CK19 combination was 100%, 100% and 1.We thus conclude that the combination of positive HBME‐1 (luminal/membranous) and CK 19 (cytoplasmic) staining on cell blocks of thyroid cytologic specimens is highly discriminatory in the diagnostic workup for papillary thyroid carcinoma. Diagn. Cytopathol. 2008; 36: 550–556. © 2008 Wiley‐Liss, Inc.