In this study, strategies for serum biomarker assessment were developed for therapeutic monitoring of HCV patients. For this purpose, serum chemokine/cytokine levels were measured by cytometric-beadarray in HCV patients, categorized according to immunotherapy response as: non-responder/NR, relapser/REL and sustained-virologic-responder/SVR. The results demonstrated an overall increase of serum chemokine/cytokine levels in HCV patients. In general, therapeutic failure was associated with presence of a predominant baseline proinfiammatory pattern with enhanced CCL5/RANTES, IFN-alpha, IFN-gamma along with decreased IL-10 levels in NR and increased IL-6 and TNF in REL. SVR displayed lower baseline proinfiammatory status with decreased CXCL8/IL-8, IL-12 and IL-17 levels. The inability to uphold IFN-alpha levels during immunotherapy was characteristic of NR. Serum chemokine/cytokine signatures further support the deleterious effect of proinflammatory baseline status and the critical role of increased/ persistent IFN-alpha levels to guarantee the sustained virologic response. The prominent baseline proinflammatory milieu observed in NR and REL yielded a restricted biomarker network with small number of neighborhood connections, whereas SVR displayed a network with integrated cytokine connectivity. Noteworthy was that SVR presented a shift towards a proinflammatory pattern upon immunotherapy, assuming a pattern similar to that observed in NR and REL at baseline. Moreover, the immunotherapy guided REL towards a profile similar to SVR at baseline. Analysis of baseline-fold changes during treatment pointed out IFN-alpha and TNF as high-performance biomarkers to monitor immunotherapy outcome. This knowledge may contribute for novel insights into the treatment and control of the continuous public health threat posed by HCV infection worldwide. (C) 2017 Elsevier B.V. All rights reserved.