VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC 50 values versus genotype 1a/1b replicons.The antiviral activity, pharmacokinetics and tolerability of VCH-759 administered as monotherapy for 10 days with a 14 day follow-up period were evaluated in 31 treatment-naı¨ve genotype 1 participants. Three cohorts received: 400mg thrice (t.i.d.), 800mg twice (b.i.d.), 800mg t.i.d or placebo.VCH-759 was well tolerated with the most frequent adverse event being gastrointestinal upset in both the active and placebo groups attributable, in part, to the dosing vehicle. VCH-759 was rapidly absorbed and trough plasma levels were at or above the IC 90 (non protein-adjusted) for all dosing regimens. The mean maximal decrease in HCV RNA log 10 (IU/mL) was 1.97, 2.30 and 2.46 for 400mg t.i.d., 800mg b.i.d. and 800mg t.i.d. doses. Viral polymerase genotypic sequencing revealed emergence of HCV variants in a majority of participants that coincided with on-treatment viral rebound.VCH-759 was well tolerated and achieved a⩾2 log 10 decline in HCV RNA with 800mg b.i.d. and t.i.d doses. In a subset of participants, viral rebound was observed and associated with resistant variants. This data supports further evaluation of VCH-759 in combination with interferon–ribavirin treatment.