Background: Histomorphology remains the gold standard in the diagnosis of thyroid tumors; specifically papillary thyroid carcinoma (PTC). However, equivocal cytohistologic features may be encountered, and warrant special criteria for distinction. Aim: This study aimed to determine the potential use of TROP-2 immunoreactivity in the diagnosis of PTC (in comparison to CK19 immunoreactivity) and its role in the segregation of PTC from non-neoplastic, benign as well as malignant thyroid lesions, and to predict the diagnostic significance of both markers in combination. Material and Methods: The current work was carried out on 249 cases of thyroid lesions, retrieved as paraffin blocks; from the Department of Pathology, Faculty of Medicine, Tanta University. The study was conducted during the period from March 2019 to May 2020. H&E staining, as well as immunohistochemical staining using TROP-2 and CK19, was performed for each case. Results: For discriminating PTC from non-neoplastic/benign thyroid lesions; TROP-2 showed 100% specificity, 87.78% sensitivity, 100% PPV and 94.47% accuracy, CK19 showed 100% sensitivity, 25.69% specificity. For segregation of PTC, from other (non-neoplastic, benign or malignant) thyroid lesions; TROP-2 showed 87.78% sensitivity, 98.11% specificity, 96.34% PPV, 93.41% NPV and 94.38% accuracy. CK19 showed 100% sensitivity and 100% NPV, yet it had low specificity of 40.25%, a low PPV of 48.65% and low accuracy of 61.85%. The combined usage of both markers didn't show better results than TROP-2 alone. Conclusions: CK19 exhibits high sensitivity over TROP-2 in PTC diagnosis, however, TROP-2 shows high specificity and better accuracy. The combination of both markers doesn't show remarkable findings than TROP-2 alone.