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Implication for health policy/practice/research/medical education: This study investigates the role of genetic heterogenity of hepatitis C virus in IFn resistance and detected 2 new genotypes 4a and 6e in Paki-stani population. Besides this an alternative therapeutic tool siRnA is presented to be used against HCV instead of IFn. This research work will be informative and useful for those who are involved in medical prevention and therapy to chronic hepatitis C. Background: Global prevalence of Hepatitis C Virus (HCV) infection corresponds to about 130 million HCV positive patients worldwide. The only drug that effectively reduc-es viral load is interferon-α (IFn-α) and currently combination of IFn and ribavirin is the choice for treatment. Objectives: The present study is aimed to resolve the genotypes based on core gene that might affect the response to interferon therapy. Furthermore an attempt was made to propose a powerful therapeutic approach by designing the siRnA from sequences of the same patients who remain resistant to IFn in this study. Patients and Methods: To achieve the objectives, a sequence analysis was performed in five HCV eLISA positive subjects who have completed IFn treatment. neighbor Joining (nJ) method was used to study the evolutionary relationship. Atomic models were pre