We conducted a prospective, controlled, multicenter trial to assess if earlier changes of serum HCV RNA levels were predictable for long-term effect, and if a short-term therapy was effective in such patients. All 377 chronic hepatitis C (CH-C) patients were treated with interferon (IFN) daily 9 MU for 4 weeks. Patients positive for HCV RNA at week 1 were treated with IFN three times weekly for additional 22 weeks (group A), while those negative for HCV RNA were randomized into either regimens; three times weekly for another 22 (group B) or 12 weeks (group C). When complete responders (CR) were defined as the subjects showing sustained loss of viremia with therapy, CR rates were 17.7% (25/141) for group A, 80.0% (36/45) for group B and 61.0% (36/59) for group C, respectively. Group B showed a significantly higher CR rate than group C, indicating that a 16-week treatment period was inadequate. Patients with CR showed a rapid decrease in virus levels by day 2 after starting therapy. The CR ratio in patients with HCV RNA levels of <1.0 Kcopy/ml by day 2 was 64.6% (82/127), while the ratio without <1.0 Kcopy/ml was 12.7% (15/118). CR ratio in patients who became negative by week 2 was 65.7%, whereas only 2.9% after week 2. The results indicate that the determination of HCV RNA levels at day 2 and the qualitative assay at week 2 with IFN are useful in predicting the therapeutic effect.