It is estimated that 51.5% of HCC cases can be attributed to HCV infection. Among them, we have to mention the polymorphisms of IL28B gene, e.g. rs12979860 C/T and rs4803217. The IL-28B gene encodes interferon-lamda 3 (IFN-λ3), which belongs to the type III IFN family including IFN-λ1, IFN-λ2, and IFN-λ3. IFN-λ interacting with a trans membrane receptor induces potent antiviral responses mediated by the activation of the JAK-STAT and MAPK pathways. IL-28B polymorphisms are linked to the efficiency of the inflammatory process during HCV infection and to the mechanisms that HCV adopts to escape by innate and adap¬tive immunity. Interestingly, since type III IFN has been found to inhibit both HBV and HCV replication in experimental models, During the last years, a number of studies have assessed the association between the IL-28B polymorphisms and risk of HCC and liver cirrhosis (LC) development in different populations; however, the results are inconsistent and inconclusive. For these reasons, a deep comprehension of the impact of IL28B polymorphisms in HCC occurrence is mandatory.