Background: Liver diseases including HCC are life-threatening morbidities. Mechanisms of HCC are still unclear. Cytomegalovirus (CMV) is DNA virus characterized by latency and cellular transformation. Genetic polymorphisms especially SNPs are the most common genetic variation. It plays a critical role in regulation of cellular interaction and cytokine production. CMV infection and its role in HCC is under investigation. Objectives: to profile IL28B single-nucleotide polymorphism in development of HCC in chronic HCV, and identify the relationship between human cytomegalovirus infection, IL28B SNPs and HCC. Methodology: 120 blood samples were obtained from HCV patients; divided according to clinical, radiological and laboratory data into three equal groups, forty patients each: HCV, HCC, LC groups, and 40 normal persons as controls. SNPs of interleukin-28 (IL28B rs12979860) by RFLP and CMV viral DNA by real-time polymerase chain reaction were investigated. Results: IL28B /CC genotype was increased significantly in controls and TT genotype in HCC group. A positive correlation among HCV viral load, CMV with the genotype IL28B rs12979860/TT especially in HCC group. Conclusions: IL28B rs12979860/TT is expressed in HCC patients making its role in development of HCC in CMV positive HCV patients cannot be denied.