The prevalence of Hepatocellular carcinoma (HCC) in Egypt represents about 11% of the gastrointestinal tract malignancies. The development of HCC usually is preceded by chronic infections with Hepatitis C virus (HCV). Interleukin-27 (IL27) is implicated in the antiviral immunity. Little is known about the use of IL27 as a biomarker for the development of HCC associated with HCV. Moreover, the role of IL-27 rs153109 gene polymorphism in the development of HCC associated with HCV has not been well studied yet. A case control study included three groups; Group I, 60 healthy control patients, Group II, 60 patients with cirrhosis associated with HCV infection, and Group III, included 60 patients with HCC associated with HCV. ELISA technique was used to measure serum IL27, while restriction fragment length polymorphism (RFLP) was used to detect single-nucleotide polymorphisms (SNP).  Results showed that the serum levels of IL27 is significantly higher in both cirrhotic and HCC groups. G allele is significantly associated with HCC and cirrhotic cases, compared with the healthy control group. Current results encourage the use of IL 27 as a diagnostic marker for both cirrhotic and HCC diseases. The aims of current work were to study the serum levels of IL27 in HCV positive hepatic patients, to evaluate its role as a biomarker for early detection of HCC, and to find any association of rs153109 with the hepatic diseases.