Pegylated interferon (peginterferon) alfa-2b plus ribavirin achieves a higher sustained response rate in patients with genotype 1 chronic hepatitis C virus (HCV) than standard combination therapy. This study evaluated HCV kinetics throughout therapy with 2 doses of peginterferon alfa-2b and ribavirin in 55 patients. Twenty-eight patients were randomized to receive a high once-weekly dose of peginterferon alfa-2b (3 μg/kg for 1 week, 1.5 μg/kg for 3 weeks, and 1.0 μg/kg for 44 weeks), and 27 patients were randomized to receive a low dose (0.5 μg/kg) for 48 weeks. Both groups also received 800 mg ribavirin daily. Mean baseline HCV RNA load, measured by reverse-transcription polymerase chain reaction, was similar in both groups (5.32 ± 0.86 log vs. 5.15 ± 1.04 log). The 3-μg/kg dose of peginterferon alfa-2b inhibited HCV RNA more significantly than the 0.5-μg/kg dose during the first 48 hours (2.08 ± 0.93 log vs. 1.09 ± 0.80 log; P < .001) and both increased at 72 hours (0.54 ± 0.73 log vs. 0.03 ± 0.36 log; P = not significant [NS]), but the high dose showed a greater reduction at the end of the week (1.07 ± 0.99 log vs. 0.72 ± 0.73 log). Both doses showed a progressive, slower viral decrease throughout therapy; however, HCV RNA became undetectable faster and in more patients with the high dose (22% vs. 7% at week 4, 56% vs. 44% at week 12, 69% vs. 63% at week 24, and 71% vs. 61.5% at the end of therapy). In conclusion, peginterferon alfa-2b/ribavirin produces an initial rapid decline in HCV RNA levels, followed by a slower, progressive decrease, similar to the biphasic kinetic profile of standard combination therapy. Higher doses of peginterferon alfa-2b also accelerate viral clearance.