To evaluate the effect of interferon alfa (IFN-alpha) on the hepatic extracellular matrix, we investigated the changes in serum N-terminal propeptide of type III procollagen during and after 4 months of INF-alpha treatment in 178 treated and 45 nontreated patients with chronic hepatitis C. Serum pretreatment levels in nonresponders were significantly higher than those in long-term and short-term responders, but those levels were not different in the latter two groups. Serum propeptide levels decreased significantly during and after IFN-alpha therapy in the treated patients, although those levels were unchanged in the nontreated patients. This decrease was sustained for 12 months after IFN-alpha was completed not only in long-but also in short-term responders and nonresponders. Serum propeptide levels decreased in those with elevated pretreatment levels, but not in those with normal initial levels, whereas serum transaminase levels decreased similarly in both groups. The changes in serum propeptide levels during and after treatment were more closely correlated with the initial levels compared with those in serum transaminase levels. These results suggested that IFN-alpha treatment induces the long-term suppression of active fibrogenesis in chronic hepatitis C independent of antiviral and anti-necroinflammatory effects, thus preventing progression to cirrhosis.