Background:Prostate cancer (PCa) is a common health problem in elderly. RAGE (Receptor for advanced glycation end products) is overexpressed in multiple human cancers. SOX2 (Sex-determining region Y box 2) also functions as an oncoprotein and promotes cancer progression but the mechanisms involved remain largely unknown. Aim:The current study investigated the expression patterns of RAGE and SOX2 in benign and malignant prostate samples in correlation with the histopathological findings in order to evaluate their role as prognostic markers or therapeutic targets. Methods:Immunohistochemical staining for RAGE and SOX2 antibodies was applied on 87 prostatic biopsies [16 of prostatitis, 20 of benign prostatic hyperplasia (BPH) and 51 of PCa]. Results:Expression of RAGE and SOX2 (percentage of positive cells) was significantly higher in PCa lesions compared with prostatitis (p<0.01) and BPH (p<0.0001) and was also significantly higher in prostatitis compared with BPH lesions (p<0.01). Also, percentage of positive RAGE and SOX2 cells showed a significant stepwise increase from Gleason Grade 3 to Grade 5 and were significantly higher in high Gleason Scores (≥8) compared to lower Scores (≤7) with statistical significance (p=0.001). Conclusion:RAGE and SOX2 were up-regulated in prostate cancer lesions, mainly in advanced grades, suggesting an active role of both antigens in the development and progression of prostate cancer and expecting the possibility of their use as therapeutic targets.