Approximately 60% of all patients with chronic hepatitis C (C-HCV) treated with standard interferon (IFN) treatment, i.e. combination of recombinant a IFN and ribavirin (RBV), are refractory to treatment. Many factors should be responsible for HCV persistence after antiviral treatment. Beside the well-known importance of some factors such as viral heterogeneity, co-infections with Hepatitis B Virus (HBV) or Human Immunodeficiency Virus (HIV), presence or absence of fibrosis, age, sex, iron overload, a greater attention is being paid to the study of viral kinetics. Observing the trend of the slope of viral decline, already after a few hours antiviral administration, it is possibile to predict the sustained virologic response and therefore to optimize therapy. As for alternative therapeutics, re-treatment with IFN alone was excluded considering the very disappointing results, whereas it seemed that the combination IFN plus RBV could recover up to 30% of the patients. Later both randomized trials and two metanalyses have demonstrated that this option is disadvantageous from the cost-effectiveness point of view since 14 patients need to be treated to obtain one responsive. The treatment combining IFN plus RBV and amantadine seems more promising. Recently trials with pegylated IFN have started with the aim to increase the therapeutical response in this category of HCV-positive patients.