Background: The main line of treatment of hepatitis C in Egypt is direct acting antiviral drugs (DAAs) Objectives: the current study aimed to explore the effect of IL28B genetic polymorphism on HCV infection progression and response to the new treatment in difficulty to treat individuals with HCV genotype 4. Methods: we collected blood samples from 50 healthy individuals as a control and 150 HCV- patients receiving SOF/DCV with ribavirin combination. IL28B (rs8099917, rs12980275) genotyping was implemented using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method to detect its impact on HCV disease outcome. Results: Out of patients, 141(94%) were responders to treatment and 9 (6%) were non- responders. A total of 112 (74.7%) of patients belonged to mild to moderate stages of liver fibrosis and 38(25.3%) had moderate to severe stages. There was a significant increase in severity of fibrosis among non-responders (p value .0.05). significant differences between the different genotypes of IL28B rs12980275 are not detected among the study population. Conclusion: TT genotype of IL28B (rs8099917) may be a protective factor against infection and associated with probability of achieving SVR to combined SOF and DCV therapy in genotype 4 HCV patients. However, GG genotype is negatively associated with HCV infection outcome. IL28B rs12980275 variants had no association with HCV infection.