Worldwide, HCC represents the sixth most common cancer and the third cause of cancer-related death. Heparanase activity is involved in cancer growth and development in humans and single nucleotide polymorphisms (SNPs) in the heparanase gene (HPSE) are associated with tumors. The studyaims to detect the association of SNPs rs12331678 in HPSE with the risk of HCC in patients with HCV-related cirrhosis. We found no significant association regarding HPSE rs12331678between the studied cirrhotic patients and controls. CA, AA genotypes, and A allele showed significant association with HCC when compared to the controls, with a higher risk to develop HCC. Also, CA, AA genotypes and A allele showed significant association with HCC when compared to cirrhotic patients, with a higher risk to develop HCC. HPSE SNP rs12331678 is more frequent in HCC patients than in cirrhotic patients or controls. This significant association is not related to the number, size of focal lesions, BCLC, or MELD score. In addition, the marked difference of HPSE SNP rs12331678 between HCCs and liver cirrhosis tissues suggests that its levels may function as a marker for the differential diagnosis of these disorders.