tBackground: Clear cell renal cell carcinoma (cc-RCC), is a serious cancer regarding; its fatality, liabil-ity for metastases and chemoresistance, so identification of recent therapeutic targets to improve thepatients prognosis is needed. SPOP is a BTB/POZ domain containing speckle-type POZ protein, has beenidentified as an E3 ubiquitin ligase component. ZEB1 is an essential epithelial mesenchymal transition(EMT) activator; E-cadherin is a cell adhesion protein that had been detected in normal epithelial cellsmembrane.Aim: Was to assess the tissue protein markers SPOP, ZEB1 & E-cadherin expressions in benign areas ofneoplastic kidney specimens and in cc-RCC patients, then correlating their expression levels with patientsclinicopathological and prognostic data.Methods: We evaluated SPOP, ZEB-1 & E-cadherin expression using immunohistochemistry in samplesfrom 50 cc-RCC and 20 benign areas of neoplastic kidney specimens, then we followed our patients for 5years and finally we have analyzed correlations between the levels of markers expressions with patientsclinicopathological and prognostic criteria in cc-RCC.Results: Positive expression of SPOP & ZEB1 in addition to negative E- cadherin expression was detectedin cc-RCC more than benign areas of neoplastic kidney specimens (p = 0.004 and p < 0.001 respectively).In cc-RCC Positive expression of SPOP, ZEB1 and negative E- cadherin expression was associated withhigher grade (p = 0.006, 0.007 & <0.001 respectively), advanced AJCC stage (p = 0.013, 0.023 & <0.001respectively), presence of L.N metastases (p = 0.002 = 0.010 and <0.001 respectively), distant metastases(p = 0.001, 0.003 & 0.035 respectively), poor PFS and OS rates (p < 0.001 and p = 0.013 respectively).Conclusion: Positive expression of SPOP& ZEB1 in addition to negative E- cadherin are associated withpoor prognosis in cc-RCC patients.