Introduction: The liver is a unique organ in the human body. Many vital functions are attributed to it. Hepatitis C is one of the most diseases which intimidate liver integrity. ITPA is a human Inosine Triphosphate Pyrophosphatase ( ITPase ), which cleaves inosine triphosphate (ITP) and xanthine triphosphate (XTP) as well as their deoxyribose forms into monophosphates. Tumor necrosis factor receptor superfamily member 10A, is a cell surface receptor that bind to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mediate the extrinsic pathway of apoptosis. Aim of the work: We aimed to clarify the association between the single nucleotide polymorphism of ITPA and TNFSF10A with the outcome of HCV infection. Subjects and method: a total of 264 subjects were recruited and classified into three main groups categorized as (I) spontaneous viral clearance (SVC) (N=55), (II)chronic HCV patients (CHCV) (N=106), and (III) control negative (N=103) where they were genotyped for SNP ITPA and TNFSF10A using allelic discrimination real-time PCR. Results: The carriage of the C allele of ITPA rs7270101 was significantly higher in HCV group compared to that of SVC (odds ratio [OR] 1.6176) and to that of controls (1.8447 ) (both P < 0.01) and carriage of C allele of TNFRSF10A (rs20575) was significantly higher in HCV group compared to that of SVC (odds ratio [OR] 2.1691 and to that of controls (2.1953 ). Conclusion: persistence of HCV infection is associated with C alleles of ITPA (rs7270101) and TNFRSF10A (rs20575) in Egyptian populations.