Among viral hepatitis, HCV is the second leading cause of hepatitis with approximately 3% carriers worldwide and 8-10 % carriers among Pakistani population. In the absence of any approved vaccine against HCV, the pegylated- interferon-alpha in combination with Ribavirin is the only standard regimen. The goal of this treatment is viral eradication to achieve sustained viral response (SVR) which means to decrease the viral titer to undetectable levels after treatment completion. However, the success rate is not hundred percent for this treatment (40- 50% for HCV genotype 1/ 4 and 75-80% for HCV genotype 2/3). Beside this fact, this treatment has several side effects that require either treatment modification or withdrawal. The present study was designed to find out the association of viral and host factors with the response of interferon treatment in chronic HCV patients of Pakistan. Two hundred CHC treatment-naïve patients from June 2011 to June 2013 were enrolled and treated with combination therapy of interferon plus ribavirin. Treatment response was analyzed by quantifying viral titer at specific interval of times during the treatment course and 6 months after treatment completion. Response rate was as followed; 81.1% patients attained Sustained virologic Response (SVR), 11.7% patients did not respond and in 7.2% patients’ virus was relapsed. It was observed that HCV genotype 3a is the most prevalent genotype followed by 1a while prevalence of mixed genotype is the least in Pakistan. Moreover, the success rate of treatment is higher in patients infected with HCV genotype 3a as compared to HCV genotype 1a. Quantification of viral load at 3rd month of treatment is valuable determinant of SVR and also helpful in tailoring the individualize treatment. As the SVR rate (93.3%) is higher in patients who achieved early viral response (EVR) as compared to those who failed to attain EVR (6.7%). It was observed that the success rate in female patients is more than male patients while rate of non-response is more in male patients than female. While no association of SVR with body mass index and age of patient was analyzed. Human genetic variations of IL28B SNPs (rs12979860, rs12980275, rs8099917, rs1181222) was identified and find out that the patients with CC genotype of SNP rs12979860 of IL28B are more likely to cure than patients with CT/TT genotype of SNP rs12979860. While the rate of NVR and relapse is higher in patients having GG genotype of SNP rs8099917. The results of multivariate logistic regression showed significant association of following factors with SVR; female gender (OR; 5.99, 95% C.I; 1.26-28.51, p= 0.024), HCV genotype 3a (OR; 9.33, 95% C.I; 1.94-44.95, p=0.005), 12 week response EVR (OR; 14.83, 95% C.I; 2.87-76.7, p=0.001) and CC genotype of SNP rs12979860 (OR; 6.39, 95% C.I; 1.18-34.7, p=0.032).