Prostate cancer is the most diagnosed cancer and the second most common cause of death among men. The incidence of prostate cancer is highest among Africans, followed by Caucasians and Mongolians. Reasons for this disparity have been attributed to differences in social, environmental, and genetic factors. In Egypt, the incidence of prostate cancer was about 4.27% of all cancers. Mechanism of action of 1, 25-dihydroxy vitamin D3 is mediated by its binding to vitamin D receptor (VDR). It functions as a heterodimer, generally with the retinoid X receptor for regulation of vitamin D target genes. Polymorphism of VDR gene exert an influence in VDR expression and mRNA stability which result in alteration in the ability of VDR protein to bind 1,25(OH)2 D3 and cause changes in the expression of regulatory genes, such as cyclin dependent kinases (CDK), which control prostatic cell division. The current study was performed to evaluate the relationship between vitamin D receptor polymorphism and prostate cancer risk among Egyptian males. Our results revealed a high statistically significant increase of PSA level among prostate cancer cases than their controls associated with VDR gene polymorphism confirmed by immunohistochemical staining of N stage and pre-treatment PSA and DKK3 in malignant cells. These observations could be used for early diagnosis of prostate cancer in men.