Chronic hepatitis C virus (HCV) infection is a worldwide etiology of hepatocellular carcinoma (HCC) particularly in Egypt. DNA‐repair systems are responsible for maintaining genomic integrity. Base excision repair (BER) is one of the major DNA‐repair pathways. The X‐ray repair cross‐complementing group 1 (XRCC1) protein encoded by XRCC1 gene is a key player in the multistep BER pathway. Deficiency in the repair capacity due to genetic alterations in DNA‐repair genes can lead to genomic instability and increased risk of cancer development. Our study aimed to investigate the association between XRCC1 gene polymorphism (rs25487) (c.28152A>G) and HCC with chronic HCV infection in Egyptian patients. The study was conducted on 35 patients with HCC and 15 patients with HCV related cirrhosis serving as pathological control group. Detection of XRCC1 gene polymorphism (rs25487) (c.28152A>G) was performed by real time polymerase chain reaction (RT-PCR). The study showed higher frequency of XRCC1 (GG, GA) genotypes and increased (G) (allele) frequency in patients with HCC compared to patients with HCV related cirrhosis. However,  the difference was statistically non-significant. Further studies on larger samples  size are required, with the need to perform DNA sequencing from tissue samples to confirm the association between XRCC1 gene polymorphism (rs25487) and HCV related HCC in Egyptian population.