Background: Thyroid cancer is the most common endocrine malignancy, accounting for 2.1% of all cases of cancer worldwide. About 77% of these cases occurring in women[1]. Approximately 90% of all thyroid cancers are differentiated; meaning that they arise from thyroid follicular cells[2]. Papillary thyroid carcinoma (PTC) is the most common histopathological type of thyroid cancer[3]. TROP-2 is a trophoblastic transmembrane  glycoprotein, also known as tumour-associated calcium signal transducer 2 (TACSTD2)  that signals cells for self-renewal, proliferation, invasion, and survival. It gives the cell stem cell-like qualities[4].P63 is a transcription factor belonging to the p53 family and shares structural and sequence homology with p53.Different studies support the hypothesis that p63 can function as a tumour suppressor, especially TAp63 isoform[5]. The aim: This study was conducted to evaluate the significance of TROP-2- and p63 expression in differentiation malignant from benign papillary thyroid lesions in thyroid histopathological biopsy specimens. Methods: Forty two  cases (21 cases of papillary hyperplasia associated lesions included (7 cases nontoxic colloid goiter, 7 cases toxic colloid goiter and 7 cases follicular adenoma) and 21 of papillary thyroid carcinoma(classic variant) were examined immunohistochemically using antibodies against TROP-2 and p63. Results: TROP-2 expression was observed in 90.5 % of cases of papillary thyroid carcinoma, while none of papillary hyperplasia associated lesions cases showed TROP-2 positivity.P63 expression was observed in 19.1% of cases of PTC, while none of papillary hyperplasia associated lesions cases showed p63  positivity. There is a statistically significant difference in TROP-2 expression between PTC and papillary hyperplasia associated lesions (P<0.001). There is no statistically significant difference in p63 expression between PTC and papillary hyperplasia associated lesions (p=0.11). Conclusion:TROP-2 was overexpressed in 90.5% of cases of PTC classic variant with specificity 100% and sensitivity 90.5% . Our results suggest that TROP-2may be considered as a useful marker in diagnosis of papillary thyroid carcinoma(classic variant). P63 was expressed in 19.1% of PTC cases with specificity 100%% and sensitivity 19%, this result suggests that p63 is less effective in diagnosis of PTC, TROP-2 and p63together can be used as diagnostic markers for papillary thyroid carcinoma.