Background: Egypt has the highest prevalence of HCV (predominantly genotype4) all over the world with 9% countrywide and up to 50% in certain rural areas. Combined PEG-IFN and ribavirin is still the only standard of care treatment in spite of its side effects, high costs and low sustained virological response rates. Hence, this provides a compelling reason for the identification of biomarker predictors of disease response to treatment. Aim: The aim of this study was to investigate the associa¬tion between these IL28B polymorphisms and the virological response in treatment of Egyptian patients infected with HCV genotype 4, which is the most preva¬lent viral isolate within Egyptian populations. Materials and Methods: rs12979860 and rs12980275 polymorphisms were studied in one hundred and twenty HCV patients by allele specific restriction enzyme digestion (RFLP technique). All chronic HCV patients were genotype 4, and were all submitted to the therapy of pegylated interferon-Alfa 2a 180 mcg per week or pegylated interferon-Alfa 2b 1.5 mcg per kg body weight in combination with ribavirin 600–1400 mg per day according to body weight for 24–48 weeks. Results: rs12979860 (CC genotype) was significantly higher in HCV cases responding to treatment and showing negative results to those not responding to treatment and showing positive results (p value<0.001).While rs12980275 (AA genotype) was significantly higher in HCV cases responding to treatment and showing negative results to those not responding to treatment and showing positive results (p value<0.001). Conclusion: Our study suggests the possibility IL 28b genes rs12979860 and rs12980275 polymorphisms carrying CC and AA genotype respectively may contribute to the susceptibility to respond to treatment of HCV Patients.