Hepatitis C virus (HCV) infection is an important cause of chronic liver disease. Standard therapy, pegylated interferon ␣ (pegIFN␣) combined with ribavirin, results in a sustained response rate in approximately half of patients. The cause of treatment failure in the other half of the patients is unknown, but viral interference with IFN␣ signal transduction through the Jak-STAT pathway might be an important factor. We have shown previously that the expression of HCV proteins leads to an impairment of Jak-STAT signaling because of an inhibition of STAT1 methylation. Unmethylated STAT1 is less active because it can be bound and inactivated by its inhibitor, protein inhibitor of activated STAT1 (PIAS1). We show that treating cells with S-adenosyl-L-methionine (AdoMet) and betaine could restore STAT1 methylation and improve IFN␣ signaling. Furthermore, the antiviral effect of IFN␣ in cell culture could be significantly enhanced by the addition of AdoMet and betaine. In conclusion, we propose that the addition of these drugs to the standard therapy of patients with chronic hepatitis C could overcome treatment resistance. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/ 0270-9139/suppmat/index.html). (HEPATOLOGY 2006;43:796-806.) H epatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. 1 Chronic hepatitis C (CHC) may lead to cirrhosis and hepatocellular carcinoma. Type I interferons (IFNs) are crucial and potent components of the early host response against virus infection 2 and recombinant pegylated IFN␣2a and IFN␣2b are widely used for the treatment of CHC and chronic hepatitis B. Current standard treatment with pegylated IFN␣ and ribavirin can cure about 50% of patients with CHC. 3,4 The cause of treatment failures in half of the patients is not fully understood, but viral interference with IFN␣