ABSTRACT: Background: The presence of diagnostic doubt in specific thyroid lesions has been extensively recorded, even among pathologists with significant expertise. This is particularly true in cases of papillary thyroid cancer (PTC), where the nuclear characteristics may be unclear. Recently, numerous molecular variations in thyroid cancer have been employed to differentiate between malignant and benign thyroid tumors. Cytokeratin 19 (CK19( and cluster differentiation 73 (CD73) biomarkers have been successfully implemented in clinical practice, leading to a substantial enhancement in the preoperative diagnosis of thyroid cancer. Objective: To assess the role of CK19 and CD73 in the diagnosis of PTC. Methodology: This hospital-based cross-sectional study took place at, New Damietta and Al-Zahraa University Hospitals. The study included 60 cases of papillary thyroid carcinoma and twelve non-neoplastic cases. The presence of immunoreactivity in each marker was evaluated and scored as negative if there was no staining or weak staining in less than 10% of the cells. Any other immunoreactivity was recorded as positive. Results: CK 19 had higher sensitivity but lowest specificity than CD73. While combination had lower specificity than CK19 alone and a sensitivity of 100%. Conclusion: Ck19 or the combination of both markers could provide the best sensitivity, while CD73 provides the best specificity at 41%.