Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is the third most frequent cause of cancer-related deaths. Secreted Protein Acidic and Rich in Cysteine (SPARC) is a matricellular glycoprotein involved in many biological processes. SPARC gene polymorphism (rs 2304052) has been shown to be associated with increased risk of hepatocarcinogenesis. Aim of the work: The aim of the present study was to investigate the association of SPARC gene polymorphism (rs 2304052) with the risk of development of HCC and its clinical utility as a genetic marker for HCC. Methods: SPARC gene polymorphism (rs 2304052) was detected in peripheral blood of 50 HCC patients on top of HCV infection, 39 patients infected with HCV and 20 healthy control subjects using Taqman Real-time PCR. Results: No statistical significant difference was found between the HCC, HCV and control groups regarding frequency of TT, CT and CC genotypes of SPARC gene polymorphism (rs 2304052) (P value = 0.2). However a statistical significant difference was found between the 3 groups regarding frequency of Tand C alleles, where the frequency of C allele was significantly more frequent in HCC group than in HCV and healthy control groups (P value = 0.05). CC and CT genotypes (risky genotypes) were associated with a statistically significant higher values of APRI test that evaluate the degree of fibrosis than TT genotype (P value = 0.04). Also CC and CT genotypes were associated with a statistically significant higher levels of AFP than TT genotype (P value = <0.001). Conclusion: There was an association between C allele (mutant allele) of SPARC gene polymorphism (rs 2304052) and HCC. Also there was an association between CC and CT genotypes (risky genotypes) and increased degree of fibrosis which represent a risk factor for HCC.