Broad proteomic profiling was performed on serum samples of phase 2 studies (PROVE1, PROVE2, and PROVE3) of the direct-acting antiviral drug telaprevir in combination with peg-interferon and ribavirin in subjects with HCV. Using only profiling data from subjects treated with peg-interferon and ribavirin, a signature composed of pretreatment levels of 13 components was identified that correlated well (R2=0.68) with subjects' underlying immune response as measured by week 4 viral decline and was highly predictive of sustained virologic response in non-African American subjects (AUC=0.99). The signature was validated by predicting in an independent cohort of non-African American subjects treated with telaprevir, peg-interferon and ribavirin (AUC=0.854). Samples from extreme responders were over-represented in these analyses. Proteins identified as differentially-expressed between responders and non-responders to HCV treatment were quantified using multiple reaction monitoring in samples from all Caucasian subjects in the peg-interferon and ribavirin arms of PROVE1 and PROVE2, revealing 15 proteins that were significantly differentially expressed between treatment responders and non-responders. Seven of the proteins are part of focal adhesions or other macromolecular assemblies that form structural links between integrins and the actin cytoskeleton and are involved in antiviral response.HCV is a significant health problem. We describe a novel approach for identifying markers that predicts HCV treatment response different treatment regimens and use this approach to identify a novel HCV treatment response signature. The signature has potential to guide optimization of HCV treatment regimens.