Core tip: The standard of care for the treatment of hepatitis C virus (HCV) infection was peginterferon plus ribavirin until the recent approval of telaprevir- and boceprevir-containing combination therapies. These HCV protease inhibitors occasionally cause HCV variants with resistance mutations. We reviewed the literature reports of resistance variants of HCV protease inhibitors in treatment-naïve patients with chronic HCV genotype 1, as well as our experience. Even in treatment-naïve patients with chronic HCV genotype 1, naturally occurring HCV protease inhibitor-resistance mutations exist in some cases. The combination of direct-acting antiviral agents against regions other than HCV NS3/4A could eradicate HCV with these resistance variants.