Vedroprevir, or GS-9451, is a potent inhibitor of the HCV NS3 protease (Box 1). NS3 is a serine protease that cleaves the HCV polyprotein and helps generate the viral replication complex. Through binding NS3, vedroprevir halts the assembly of the viral replication complex, thus interfering with the assembly and release of viral particles. Vedroprevir is a potent inhibitor of NS3 protease with high selectivity against off-target proteases. It has rapid association kinetics and slow dissociation kinetics. Preclinical studies of vedroprevir showed high oral bioavailability in rats, dogs, and monkeys. Preclinical studies of vedroprevir demonstrated potent NS3 inhibition using laboratory strains as well as patient-derived NS3 protease gene isolates. In a phase I, randomized trial of vedroprevir monotherapy, doses of 200 and 400 mg/day yielded median maximal HCV RNA reductions of −3.2 log10 in genotype 1a patients and −3.5 log10 in genotype 1b patients. Significantly less activity was seen against genotype 2a HCV when compared to genotype 1. Vedroprevir was not listed on the Gilead Sciences pipeline in its 2014 annual report and appears to have been discontinued for the once-daily treatment of Hepatitis C.