Abstract Background Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide and the fourth in Egypt. Persistent inflammation and specific somatic mutations in driving genes play major role in the development of HCC. One of these somatic mutations is CTNNB1 mutations with subsequent activation of ß-catenin in HCC, associated with a risk of malignant transformation. In this study, we investigate the clinical utility of peripheral blood circulating tumor DNA (ctDNA) CTNNB1 SNP (rs121913407) (c.133T>C) in HCC patients compared to pathological chronic hepatitis C virus (HCV) patients and healthy controls. Aim of the Work The aim of this work is to study the clinical utility of peripheral blood ctDNA to assess CTNNB1 SNP (rs121913407) (C. 133T>C) in HCC patients and the results will be compared to findings in pathological (Chronic Hepatitis C virus patients) and healthy controls. Patients and Methods Case-control study at Ain Shams Centre for Organ Transplantation, Ain Shams University Hospitals, enrolling twenty-eight adult HCC patients (twelve early HCC patients and sixteen advanced HCC patients), ten patients with chronic hepatitis C as a pathological control group, and ten healthy controls, plasma were collected, and stored at -80 °C. Detection of mutations in the gene locus CTNNB1 rs121913407 (c.133T>C) was done by Real-time PCR. Results There was statistical significant difference between early and late cases of HCC as regards AFP, AST however, all of our studied cases (early and advanced HCC) in addition to HCV and healthy control groups were CTNNB1 wild (TT) genotype. Conclusions None of our recruited subjects showed CTNNB1 rs121913407 gene mutation. Further studies on larger number of patients are needed to clarify and confirm the clinical utility of CTNNB1 Polymorphism (rs121913407) in the pathogenesis of HCC related to HCV in Egyptian population.