In thyroid, the diagnosis of papillary carcinoma (PC) is based on nuclear features; however, identification of these features is inconsistent and controversial. Proposed markers of PC include HBME-1, specific cytokeratins (CK) such as CK19, and ret, the latter reflecting a ret/PTC rearrangement. We applied immunohistochemical stains to determine the diagnostic accuracy of these three markers. Formalin-fixed, paraffin-embedded tissue from 232 surgically resected thyroid nodules included 40 hyperplastic nodules (NH), 35 follicular adenomas (FA), 138 papillary carcinomas (PC; 54 classical papillary tumors and 84 follicular variant papillary carcinomas [FVPC]), 4 follicular carcinomas (FC), 6 insular carcinomas (IC), 7 Hürthle cell carcinomas (HCC), and 2 anaplastic carcinomas (AC). HBME-1 and ret were negative in all NH and FA; some of these exhibited focal CK19 reactivity in areas of degeneration. Half of the FC and AC exhibited HBME-1 staining but no positivity for CK19 or ret. In PC, 20% of cases stained for all three markers. Classical PC had the highest positivity with staining for HBME-1 in 70%, CK19 in 80%, and ret in 78%. FVPC were positive for HBME-1 in 45%, for CK19 in 57%, and for ret in 63%; only 7 FVPC were negative for all three markers. The six IC exhibited 67% staining for HBME-1 and 50% positivity for CK19 and ret. The seven HCC had 29% positivity for HBME-1 and CK19, and 57% positivity for ret. This panel of three immunohistochemical markers provides a useful means of diagnosing PC. Focal CK19 staining may be found in benign lesions, but diffuse positivity is characteristic of PC. HBME-1 positivity indicates malignancy but not papillary differentiation. Only rarely are all three markers negative in PC; this panel therefore provides an objective and reproducible tool for the analysis of difficult thyroid nodules.