Background Hepatitis C virus (HCV) infection is the main risk factor for chronic hepatitis (CHC), liver cirrhosis, and hepatocellular carcinoma (HCC). B cell lymphoma-2 (BCL-2) prevents apoptosis, and its overexpression could promote cancer cell survival. Purpose To evaluate the association of Bcl-2 gene polymorphism (rs2279115) and HCV-related HCC susceptibility. Subjects and methods Two hundred and seventy individuals included in this case-control were divided into three groups. Group I: It included 90 apparently healthy subjects as control. Group II: It includes 90 patients with chronic HCV hepatitis. Group III: It includes 90 patients with HCC with positive HCV. Bcl-2 gene polymorphism (rs2279115) C > A genotypes by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). Results There are significantly higher incidence of CA and AA genotypes in HCV patients with HCC compared with those without HCC (OR 2.3, %CI (1.2–4.6), P = 0.01 and OR 5.7, %CI (2.4–13.8), respectively) and compared with control group (OR 2.9, %CI (1.5–5.8), P = 0.002 and OR 7.1, %CI (2.9–17.4), P < 0.001, respectively), while no significant difference between the control and HCV patients without HCC groups (OR 1.2,%CI (0. 7–2.4), P = 0.48, for CA, and OR 1.2, %CI (0.4–3.3), P = 0.67, for AA).The frequency of A allele was highly significantly overrepresented in the HCC group in comparison to HCV group (53.3% versus 30.6%, P < 0.001) and control group (53.3% versus 27.2%, P < 0.001) but no significant difference (p = 0.49) between control group and HCV patients. Conclusion This study demonstrated that Bcl-2 gene polymorphism (rs2279115) was associated with increased susceptibility to HCV-related HCC.