Since the discovery of its broad antiviral activity back 40 years ago1 and as new therapeutic indications are foreseen against emerging viruses, 2 ribavirin (RBV), a synthetic triazole analogue of guanosine, has not yet revealed all the secrets of its mechanism of action. Despite this lack of knowledge, RBV has been a critical component of the standard of care ‘dual’therapy, that is, α-interferon (IFNα) and then pegylated-IFNα (PEG-IFNα) plus RBV, for the treatment of tens of thousands Hepatitis C Virus (HCV)-infected patients worldwide for almost 20 years. 3

Several, quite diverse, modes of action have been proposed including:(1) a direct inhibitory effect on viral RNA-dependant RNA-polymerases;(2) lethal mutagenesis of viral nucleic acids;(3) depletion of the cell guanosine triphosphate pool by inhibiting the enzymatic activity of the inosine monophosphate dehydrogenase;(4) modulation of the Th1/Th2 T lymphocyte balance;(5) impairment of the translation via eIF4E inhibition. None of the proposed mechanisms of action convincingly explains RBV-mediated potentiation of IFN-based therapy in HCV-infected patients and, although they are not mutually exclusive, they are all still a matter of controversy (see ref 4 for review). Whereas RBV used in monotherapy has shown little or no effect on HCV viremia5 or HCV genetic heterogeneity, 6 it is worth noting that about 50% of the patients undergoing long-term RBV monotherapy display a strong reduction in serum alanine aminotransferase (ALT) and an improvement in liver histology, indicating that RBV alone might have some effect in controlling the progression of chronic hepatitis C. 7 These observations also point towards possible indirect mechanisms of