Hepatitis C virus (HCV) persistently infects more than 175-185 million people globally. Drug résistance to anti-HCV DAAs therapeutics particularly NS3/4A has been a major concern for efficacy of HCV treatment due to  generation of HCV quasispecies. Risk determination of the resistance of HCV to anti-NS3/4A inhibitors was accomplished using ViPR algorithm that computes and analyzes resistance-associated amino acid substitutions in HCV NS3 protein target site and reveal altered response to NS3/4A PIs. Spot comparison and data visualization was carried out using ncbi.nlm.nih.gov protein sequence graphics and R-package for Ubuntu version 12.04. Resistance to multiple NS3/4A PIs (telaprevir, simeprevir, faldaprevir and asunaprevir) was exhibited by HCV genotype 1 variant D1194A/E/T/G-NS3 (a substitution hot spot) while the risk of resistance to telaprevir (V1062 L NS3 variant) and simeprevir (S1148R variant) was demonstrated by HCV genotype 2. Genotype 3 & 4 revealed resistance against only telaprevir. Another almost pan-genotype (genotype 2,3,4,5 and unclassified) substitution hot spot was identified as anti-telaprevir variant V1062 L. Single substitution conferring multiple anti-NS3/4A PIs resistance was observed in D1194A NS3 variant (anti-simeprevir, anti-faldaprevir, anti-asunaprevir in genotype 1), Q1106K NS3 variant (anti-simeprevir, anti-faldaprevir in genotype 5 and 6) and T1080S NS3 variant   (anti-faldaprevir, anti-telaprevir in genotype 5 and unclassified NS3 sequence). In addition to that, variant S1148G exhibited increased sensitivity to simeprevir in case of genotype 1. Because of a higher degree of HCV genomic variability, NS3 variants with decreased susceptibility to NS3/4A PIs exists, and therefore the resistance profile along with potency, adverse effect of PIs is noteworthy and should be well-considered while developing different protease inhibitors for effective treatment of HCV patients.