R ibavirin (1-b-d-ribofuranosyl-1,2,4-triazole-3carboxamide; RBV) is a guanosine analog with broad-spectrum virustatic activity originally developed for the treatment of severe respiratory syncytial virus infection. The drug has since been empirically used, with varying degrees of proven clinical efficacy, for the treatment of several RNA virus infections, including Lassa fever and other arenaviruses, Crimean-Congo hemorrhagic fever, La Crosse encephalitis, influenza, adenovirus, and hepatitis E virus (reviewed in earlier studies). However, beneficial effects in these clinical settings are often controversial, and clinical trials are, for obvious reasons, largely missing.Various mechanisms of action of RBV have been suggested, including direct inhibition of viral RNAdependent RNA polymerases, inhibition of host inosine monophosphate dehydrogenase, inhibition of viral capping enzymes, and, last but not least, induction of lethal mutagenesis (i.e., the point at which the number of mutations per genome is too large to allow viability of newly assembled virions). However, the overwhelming success of RBV largely derives from its excellent performance in synergy with standard or pegylated interferon-alpha (Peg-IFN-a)-based therapies leading to dramatic improvement in sustained virological response (SVR) rates among patients with chronic hepatitis C virus (HCV) infection, which has been extended to combination treatment with firstand second-generation direct-acting antivirals, and, very recently, to interferon (IFN)-free regimens. Although the predominant mode of action of RBV in HCV infection was shown to consist in a modest and transient, even though significant, reduction of viral replication, several lines of experimental evidence pointed to concomitant immunomodulatory effects, particularly on adaptive immune responses, by tipping the balance toward a T-helper (Th)1 cytokine profile, increasing IFN-c production in vitro, and reversing T-regulatory (Treg)-mediated suppression of CD4 effector T cells through inhibition of interleukin (IL)210 secretion by Treg cells. However, these findings in vitro were not replicated in vivo, because IFNc-producing T cells were instead reduced in patients treated with IFN-a/RBV combination. Interestingly, hepatic expression of interferon-stimulated genes (ISGs) is up-regulated in nonresponders and it has been shown that RBV decreases expression of ISGs, possibly restoring their responsiveness to exogenous IFN. This interpretation is supported by a modest, but significant, increase in ISG up-regulation in patients treated with PEG-IFN-a/RBV, compared with IFN-a alone, suggesting a role for RBV as a modulator of innate immunity. These findings indicate numerous potential clinical applications of RBV as an immunomodulator. However, a randomized, controlled clinical trial of Peg-IFN-a with or without RBV in a chronic DNA viral infection, such as hepatitis B virus (HBV), failed to show a beneficial effect of combination versus Peg-IFN-a monotherapy, implying that RBV-mediated immunomodulation alone would be insufficient as adjuvant treatment of any viral infections. Whether this is a result of the fact that many ISGs are already down-regulated in chronic HBV infection so that RBV would provide no additional benefit remains to be determined. Natural killer (NK) cells are a major component of the innate immune system that are instrumental in establishing a coordinated and efficient adaptive immune response in viral infections. Most studies suggest that they are functional and activated in the peripheral blood of patients with chronic HCV infection, but are polarized toward cytotoxicity as a consequence of chronic exposure to endogenous IFN-a, resulting in deficient IFN-c secretion. This is caused by a prevalent phosphorylation of signal transducer and activation Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; IFN, interferon; IL, interleukin; ISGs, interferon-stimulated genes; NK, natural killer; NS, nonstructural protein; Peg-IFN-a, pegylated interferon-alpha; pSTAT, phosphorylated signal transducer and activator of transcription; RBV, ribavirin; STAT, signal transducer and activator of transcription; SVR, sustained virological response; Th, T helper; TRAIL, tumor necrosis factor–related apoptosisinducing ligand; Treg, T-regulatory cell. Address reprint requests to: Mario U. Mondelli, M.D., Ph.D., F.R.C.P., Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Via Taramelli 5, 27100 Pavia, Italy. E-mail: firstname.lastname@example.org; fax: 139 0382 526450. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27186 Potential conflict of interest: Nothing to report.