Background: Genetic variations may play an important role in the development of HCC in HCV patients. Variants of IL23R gene were investigated for association with many diseases like chronic inflammatory disorders, RA, inflammatory bowel diseases and the susceptibility to the development of gastric cancer but no data are available concerning the association of IL23R gene (rs11209026) polymorphism with HCC development in HCV patients. Therefore, the current study aimed to analyze this polymorphism within the gene to evaluate its contribution to chronic HCV susceptibility and/or HCC development in Egyptian patients. Subjects and methods: One hundred and ninety-two patients with chronic HCV infection were included in this study (92 of them without HCC and 100 of them with HCC). One hundred healthy control subjects with no history of previous liver disease (HBV and HCV infection were negative) were included in the study. The IL23R polymorphism (rs11209026 G>A) were genotyped by real time PCR. Results: We found a significant lower incidence of GA and AA genotype in HCV patients with HCC compared to those without HCC (p = 0.026 and 0.040 respectively) and compared to control group (p =0.008 and 0.007 respectively). While, no significant difference between control and HCV patients without HCC groups was found. Conclusions: Our study suggests that wild type IL-23R GG serves as a risk factor for HCC and supports for the protective role of the rare variant rs11209026 (Arg381Gln) against HCV-related HCC in Egyptian patients.