As combination therapy with peginterferon (PEG-IFN) and ribavirin has a high morbidity, identifying individuals with hepatitis C virus (HCV) who will not respond to the treatment would be beneficial. The early responses of serum HCV RNA levels to standard interferon (IFN) and PEG-IFN were examined to determine if it was possible to identify resistance to combination therapy. One hundred thirty-one patients infected with HCV genotype 1b were enrolled. Patients were given 6 MU of standard IFN alpha-2b at least 2 weeks before initiating combination therapy. Serum HCV RNA levels were measured before, 24 hr after the administration of standard IFN, and 24 hr after the administration of PEG-IFN (at the start of the combination therapy). The association between reductions in HCV RNA levels at 24 hr after the administration of standard IFN and PEG-IFN and the outcome of combination therapy were analyzed. Reductions in HCV RNA levels were poorer in patients who did not respond than in those with a sustained virologic responses or relapses (P < 0.0001), both 24 hr after the administration of standard IFN and 24 hr after the administration of PEG-IFN. Reductions in HCV RNA levels 24 hr after the administration of standard IFN were an independent factor associated with non-response by multivariate analysis. An early reduction in viral load to a single administration of standard IFN is a useful predictor of non-response in patients with HCV genotype 1, allowing for pretreatment identification of patients who will not benefit from combination therapy.