Mutations in several subgenomic regions have been implicated in influencing response to interferon therapy; however, a comprehensive picture of Indian patients was lacking. Based on the viral load and clinical factors, 10 out of 15 patients were found to be complete responders, whereas 5 patients were nonresponders. The pretreatment viral RNA load of the patients was found to be between 5.20 and 6.13 log 10 IU/ml, which eventually fell to 2.77 log 10 IU/ml after 24 weeks of treatment, whereas in the case of nonresponders, the average was 5.38 log 10 IU/ml. In order to study the influence of the hepatitis C virus genotype on the response to interferon therapy, the 5′ untranslated region sequences of the samples were analyzed, which showed that genotype 3 patients responded better than genotype 1 patients. Additionally, the mutations in the interferon sensitivity-determining region (ISDR) of the NS5A protein and the double-stranded RNA-activated protein kinase-eukaryotic initiation factor 2 alpha phosphorylation homology domain (PePHD) of the E2 envelope protein, before and after treatment, were compared with nonresponder prototype J. Although, no clear correlation was found in the case of the mutated ISDR, some significant changes in residues were observed in the PePHD region, which could be helpful in understanding the molecular basis of resistance to therapy. Interestingly, analysis of the quasispecies variations showed a change in genotype in one sample during treatment, which might have contributed to the resistance. The results suggest that the mutations in different regions of the viral genome might have a concerted effect on the response to interferon therapy.