Cancer prevalence is critically increasing worldwide; accordingly, improved prediction and therapeutic tools are necessary. Interleukin (IL)‐21 is a potent antitumor cytokine, and the relationship between its gene variations and cancer risk is well established. Nevertheless, so far no study has investigated its role in hepatocellular carcinoma (HCC) progression and metastasis in hepatitis C virus (HCV)‐infected people. Therefore, the present investigation was led on 267 Egyptian participants, involving 177 patients with HCV of which 90 patients had HCC (HCC group), 87 patients without HCC (non‐HCC group), and 90 unrelated healthy controls. The association between rs2221903A/G and rs2055979G/T of the IL‐21 gene and the risk of HCC and metastasis, as well as the clinico‐pathological features, were analyzed. While rs2221903A/G polymorphism was not polymorphic in our cohort, patients carrying the genotype TT and allele T of the rs2055979G/T polymorphism had a significantly lower risk of HCC when comparing with HCC group and healthy controls. Also, participants carrying the aforementioned genotype and allele had a significantly lower risk of metastasis when comparing metastatic group with both nonmetastatic group and control group. The rs2055979G/T polymorphism was not significantly associated with clinico‐pathological features of HCC. This is the first study to report a relationship between an intronic polymorphism in IL‐21 gene and HCC and metastasis risk in the Egyptian people, in addition to identifying a potential new marker for the early detection and treatment of HCC.