OBJECTIVE Interferon is the only established treatment for chronic hepatitis C but the host-dependent or virus-related factors affecting the response rate to interferon therapy are not yet clear. The purpose of this study was to investigate the factors predictive of response to interferon-alfa therapy in chronic hepatitis C. METHODS Twenty-five consecutive patients with chronic hepatitis C were randomized to three regimens of interferon-alfa: group A (n = 7, 3 MU every day for 3 months), group B (n = 8, 3 MU every other day for 3 months) and group C (n = 10, 3 MU every other day for 6 months). We quantified serum HC RNA levels by competitive reverse transcription-polymerase chain reaction (RT-PCR) and performed HCV genotyping using type-specific primers deduced form the NS5 region of the HCV genome. We also attempted to identify which demographic, biochemical and histologic factors in addition to virus-related factors would significantly predict beneficial response to interferon by multivariate analysis. RESULTS Sustained responders were 8 (36.4%), nonsustained responders were 2 (9.1%) and nonresponders were 12 (54.5%) of 22 patients who had received complete therapy. The initial HCV RNA level (logarithmic transformed copy numbers per ml of serum) in sustained responders (5.75 +/- 0.39) was significantly lower than that of nonsustained responders (6.80 +/- 0.71) and nonresponders (6.70 +/- 0.52) (p < 0.05). In multivariate multiple logistic regression analysis, the serum HCV RNA level before therapy was only the independent predictor of a sustained response to interferon-alfa therapy (p = 0.001). CONCLUSIONS Serum HCV RNA level before therapy was the most useful predictor of a sustained response to interferon-alfa therapy for chronic hepatitis C.