This study was aimed at searching noninvasive markers of the transition from mild to severe fibrosis stage in HCV patients undergoing hepatic fibrosis. Thirty-three patients affected by chronic HCV vs. twenty healthy donors were evaluated for the serum levels of several circulating matrix metalloproteinases (MMPs), TRAIL and β-NGF by multiplex biometric ELISA based immunoassay and anti- and pro-oxidant status (d-ROMs, BAP and NO) using a Diacron automated method. HCV patients displayed increased expression levels of MMP-8, MMP-9, TRAIL and β-NGF, and an imbalance between pro- and antioxidant status, that contribute to liver fibrosis. Since the determination of these parameters represents a reliable and easily applicable method, these parameters are suggested as serum surrogate markers for HCV patients in the routine clinical practice. ► Chronic HCV infection is characterized by different degrees of fibrosis. ► MMP-8 and MMP-9 are up-expressed in HCV patients with different stages of fibrosis. ► An imbalance between pro- and antioxidant status in HCV patients. ► TRAIL and β-NGF are up-expressed in HCV patients with different stages of fibrosis. ► All these parameters can be used as markers for HCV patients.