Ubiquitin-specific peptidase 22 (USP22) is described as a stem cell (CSC) marker which is involved in many biological processes, including cancer development, cellular growth and differentiation. Sirtuin 1 (SIRT1) controls a set of biologic processes that range from metabolic homeostasis to cancer. E-cadherin is a calcium dependent intercellular adhesion molecule. Clinically, USP22, SIRT1 and E-cadherin have been studied to predict prognosis of a variety of cancers but the detailed roles of their expression in papillary thyroid cancer (PTC) and their relation to cancer invasion, metastases and recurrence are still not fully explained. Aim of the study: To evaluate the expression of USP22, SIRT1 & E-cadherin in PTC tissues and adjacent nonneoplastic thyroid tissue and to correlate their expression with histopathology, clinical, pathological and prognostic parameters of PTC patients. Methods: We have assessed USP22, SIRT1 & E-cadherin expression using immunohistochemistry in 40 cases with PTC in both malignant tissue and adjacent non-neoplastic tissue, analyzed the relationships between their levels of expression, clinic-pathological parameters, prognosis and survival of patients. Results: High protein expression levels of both USP22, SIRT1 in addition to low E-cadherin expression in PTC were associated with larger tumors, extra-thyroidal extension, vascular invasion, lymphatic spread (p < 0.001), existence of distant metastases (p = 0.005 & 0.012 respectively), higher stage of the disease (p = 0.012 & 0.042 respectively) and worse five-years overall survival rates (p < 0.001). Conclusion: Patients having advanced PTC with unfavorable prognosis had high levels of both USP22, SIRT1 in addition to low E-cadherin expression.