Our aim was to study the effect of ribavirin on viral kinetics and to study the early patterns of response to antiviral therapy of hepatitis C and their correlation with interferon pharmacokinetics and pharmacodynamics. We conducted a randomized, controlled trial of peginterferon alfa-2a with or without ribavirin in interferon naïve patients with HCV genotype 1. HCV RNA levels were measured at frequent intervals during treatment together with serum levels of peginterferon alfa-2a and 2'5'oligoadenylate synthetase (OAS). Of 29 patients treated, 14 had a complete response at day 29 while 15 had a null response (less than 1 log decline in HCV RNA). There were no significant differences between complete and null responders with regard to gender, age, race, body mass index, HCV subtype, baseline HCV RNA levels, serum aminotransferase activities, stage of fibrosis, peak OAS, or interferon levels. Mean serum IFN levels at day 29 and OAS levels at day 3 were no different between complete and null responders (15,525 vs. 30,768 pg/ml and 2,044 vs. 2,323 pM/hr, respectively, P = n.s.). Addition of ribavirin to pegylated IFN did not significantly affect day 29 IFN levels or Day 3 OAS levels. In conclusion, null responders to either peginterferon alone or in combination with ribavirin have little or no decrease in serum HCV RNA early in therapy and rarely go on to achieve sustained virologic response and have no apparent host differences than complete responders, suggesting that interferon resistance in these patients may be virally rather than host-determined.