This study evaluated the relationship between developing interleukin-23 receptor (IL- 23R) gene polymorphism and hepatitis C-related hepatocellular carcinoma (HCC) in Egyptian patients. Patients & Methods: The current study included 250 subjects. They were divided into three groups: one hundred patients with hepatitis C virus (HCV) infection without HCC, one hundred patients with HCV and HCC, and fifty healthy non-hepatic volunteers as a control group. IL- 23R gene polymorphism (rs10889677) was genotyped by restriction fragment length polymorphism- polymerase chain reaction (RFLP- PCR). Results: There was a significant difference between the studied groups regarding the frequency of genotypes and alleles (P =0.006 and < 0.001, respectively). Additionally, under the recessive inheritance model, IL-23R polymorphism is significantly associated with HCC development (P=0.001). Moreover, a significant protective effect of the rs10889677 C allele in HCC susceptibility was detected (OR = 0.15, 95% CI = 0.05–0.39, P < 0.001). AC and CC genotypes also had a significant protective effect (OR = 0.16, 95% CI = 0.05–0.46, P < 0.001). Conclusions: there is a possible relationship between IL- 23R (rs10889677) polymorphism and HCC risk in Egyptian individuals where AC and CC genotypes and C alleles are protective