Previous studies have shown that the total perihepatic lymph node (PLN) volume is (1) associated with the extent of inflammatory activity in the liver and (2) changes according to the antiviral response in patients receiving interferon-based therapy for chronic hepatitis C (HCV) infection. The aim of this prospective pilot study was to examine whether the total PLN volume similarly changes in patients receiving antiviral monotherapy with the protease inhibitor telaprevir (VX-950). The present study was conducted in a subgroup of 19 patients with chronic hepatitis C genotype-1 infection treated with the protease inhibitor telaprevir (VX-950) or placebo in a phase Ib clinical trial. The total perihepatic lymph node volume was assessed using sonography before the initiation of antiviral therapy, at the end of 14 d of treatment, and at follow-up. Treatment with telaprevir resulted in a significant reduction of plasma HCV-RNA in all patients at the end of 14 d of treatment. In patients receiving telaprevir, the total PLN volume decreased significantly at the end of 14 d of treatment compared with pretreatment volume (1.26 mL to 0.76 mL, p=0.01). In contrast, no significant difference was seen in patients receiving placebo (1.00 mL to 1.06 mL, p=0.26). These results suggest that the perihepatic lymph node volume can be used as an indicator for viral and histologic response not only as previously reported in patients receiving interferon-based therapy, but also in patients receiving therapy with direct antivirals.