Hepatitis C virus (HCV) is a blood-borne virus and a principal source of liver cirrhosis, chronic hepatitis, and hepatocellular carcinoma (HCC). Approximately 180 million people, around 3% of the world’s population infected with HCV. Roughly, 10 million Pakistanis, representing 6% of the total population, are with HCV infection. Most HCV infections lead to chronic infections due to the failure of the immune response. Toll like Receptors (TLR) is a family of transmembrane proteins that expresses most of the immune cells and is the main component of innate immunity that perform an important role in the recognition of various types of pathogens. The major innate immune sensor TLRs (TLR2, 3, 4, 7, 8, and 9) and Retonicacid inducible like receptor (RLR) (MDA5) are important for viral nucleic acid detection and inducing antiviral reactions. Aberrant immune activation can be harmful to the host; Therefore, TLRs and RLR activities are strictly regulated by the immune system. In addition, an unbalanced inflammatory response to the host via a TRL or RRL based signaling pathway may be responsible for inflammation and autoimmune disease.” “In this studyTLR2, 3, 4, 7, 8, 9 and MDA5genes Polymorphism were analyzed to ensure that these genes may play a role in the failure of interferon therapy and HCV clearance. In TLR2 Polymorphisms, we analyzed SNP Arg677Trp and Arg753Gln. The polymorphisms of TLR3 we analyzed were SNP rs5743314 (G/C), rs78726532 (A/G) and rs3775290 (T/C). The TLR4 polymorphism, analyzed in our study was SNPrs4986790(C/T), TRL7 rs179009 (A/G), TLR8 rs3764879, TLR9 rs187084 (A/T), TLR9 rs5743836, MDA-5 rs1990760 (A/G).High resolution melting (HRM) curve method was applied to screen out the mutations.PCR was directed according to the protocols of Step OnePlus™ Real-Time PCR.Total 500 samples were collected (400 HCV patients and 100 healthy subjects). Out of 400 HCV patients, 323 were interferon responders and 77 were interferon nonresponders.TLR2 Arg677Gln, TLR3 rs3775290, TLR4 Asp299Gly, TLR7 rs179009 and TLR9 rs187084 shown significant association with HCV recurrence, while TLR2 Arg753Gln, TLR3 rs5743314 and rs78726532, TLR8 rs3764878, TLR9 rs5743836 and MDA5 rs1990760 did not show any association with HCV recurrence.” Our outcomes are inconsistent with the current positional data on the NCBI database. These genotypes may help to identify those patients at higher risk of developing complications during the first year of treatment. Outcomes of this study may have opened a door to set up prospectively planned randomized controlled trials (RCTs) that include TLRs genotype information while evaluating new and advanced treatments of HCV especially for patients infected with genotype 3.Finally, the outcomes of this study may result in a benefit for the patient when clinically use to improve the efficiency and immunogenicity of the current therapeutic regimens through combining therapy with alternate TLR agonists to overcome immune deficiencies induced by defective TLR signaling.