Recent studies have demonstrated that polymorphisms near the interleukin-28B (IL-28B) gene could predict the response to Peg-IFN-a/RBV combination therapy in HCV-infected patients. The aim of the study was to correlate the serum level of IL28B in HCV-infected patients with virus genotype/subgenotype and disease progression. IL28B serum level was detected and variations at five single nucleotide polymorphisms (SNPs) in IL28B gene region were genotyped and analyzed. The variation of IL28B genetic polymorphisms was found to be strongly associated with HCV infection when healthy control group was compared to HCV-infected patients with all P values <0.0001. Functional analysis revealed that subjects carrying rs8099917-GG genotype had higher serum level of IL28B than those with GT or TT genotypes (P = 0.04). Also, patients who were presented with cirrhosis (Cirr) only or with cirrhosis plus hepatocellular carcinoma (Cirr+HCC) had higher levels of serum IL28B when compared to chronic HCV-infected patients (P = 0.005 and 0.003, resp.). No significant association was found when serum levels of IL28B were compared to virus genotypes/subgenotypes. This study indicates that variation at SNP rs8099917 could predict the serum levels of IL28B in HCV-infected patients. Furthermore, IL28B serum level may serve as a useful marker for the development of HCV-associated sequelae.