Papillary thyroid carcinoma (PTC) represents the most common primary malignant thyroid tumor and its diagnosis is dependent on the presence of classic nuclear features that are sometimes seen in some non-neoplastic and benign lesions. Several immunohistochemical markers are used individually or in combination to help in differentiation of PTC from mimickers. The aim of the current study was to assess the diagnostic value of TROP-2 and cytokeratin 19 (CK19) expression in differentiating PTC from other mimickers both singly and in combination. The current study was carried out on 77 surgical specimens (56 PTC and 21 non-neoplastic cases) and 12 cytological specimens (4 THY2, 6 THY4, and 2 THY5). TROP-2 was negative in 81% of non-neoplastic surgical specimens and in 100% of THY2 cytological specimens while it was positive in 71.4% of PTC surgical specimens and 100% of THY4/THY5 cytological specimens. Sensitivity and specificity of TROP-2 positive expression for diagnosis of PTC in surgical specimens reached 71% and 81%, respectively, while it reached 100% for both in cytological specimens. Cytokeratin 19 showed positive expression in 85.7% of non-neoplastic surgical specimens and in 92.9% of PTC surgical specimens. Cytokeratin 19 showed negative expression in 75% of Thy2 cases while it was positive in all studied Thy4 and Thy5 cases. Sensitivity and specificity of CK19 total estimated score for diagnosis of PTC in surgical specimens were 78.6% and 66.7%, respectively, while it reached 100% and 75% in cytological specimens. Positive TROP-2 and CK19 expression in PTC were associated with lymph node metastasis. TROP-2 is a specific rather than sensitive marker while CK19 is a sensitive rather than specific marker in differentiating PTC from other mimickers in surgical specimens. The diagnostic validity of both markers was superior in diagnosis of classic PTC compared with follicular variant PTC. TROP-2 is superior to CK19 in diagnosis of PTC in cytological specimens. Both TROP-2 and CK19 could be used preoperatively in adjunct to hematoxylin and eosin for more confident diagnosis of thyroid cytology and along with radiology as predictors of lymph node metastasis.