Abstract: Background and Objective: Vitamin D, considered as a systemic hormone and important immune modulator, has emerging roles in fibrogenesis, cell cycle arrest and cancer development. The objective of this study was to investigate the association between the Vitamin D Receptor (VDR) gene polymorphisms and hepatocellular carcinoma (HCC) development and severity in Egyptians with Chronic Hepatitis B (CHB). Methods: Two hundred and eighty-five adult consecutive outpatients were enrolled, of which 108 patients with CHB and HCC, 92 patients with CHB without HCC and 85 patients with HCC without CHB. Evaluation of clinicopathological characteristics of HCC was done. Genotyping of VDR gene at TaqI, BsmI, ApaI and FokI was also performed. Results: FokI TT genotype prevalence and T allele frequency were higher in HCC patients than those without HCC. Patients carrying FokI TT genotype had significantly higher risk for HCC (p <0.05) after using FokI CC genotype as a reference and adjusting other covariates including age, gender, CHB infection time, family history of cancer and serum ∞-fetoprotein levels. Also, patients carrying FokI TT genotype had advanced disease stage of cancer, liver cirrhosis, lymph node metastasis. Conclusion: Only the SNPs of VDR gene at FokI locus (C>T) could be used as a molecular marker predicting the risk and evaluating the severity of HCC in Egyptian patients infected with CHB. Polymorphism at FokI locus was associated with increased HCC susceptibility and has a significant role in the determination of its clinicopathological characteristics.