OBJECTIVE The response to interferon therapy for chronic hepatitis is known to decrease with progression of the hepatic fibrosis. On the other hand, serum hyaluronate reflects hepatic sinusoidal capillarization or liver cirrhosis, and also serum type IV collagen, which is one of the main components of the basement membrane, rises with the progression of hepatic fibrosis. In this study, the relationship between the degree of hepatic fibrosis and the response to interferon-alpha was determined retrospectively in patients with chronic hepatitis C. In addition, whether the measurement of serum hyaluronate and type IV collagen before interferon-alpha therapy was useful for predicting the response to interferon-alpha therapy in chronic hepatitis C was determined. METHODS Thirty-seven patients with elevated serum ALT levels for at least 6 months and histologically determined chronic hepatitis were studied. All patients were positive for anti-HCV and negative for hepatitis B surface antigen. Twenty-eight healthy adults with normal blood biochemical data, who were negative for hepatitis B antigen and HCV antibody tests, had limited alcohol intake were used as controls. The test group was given IFN-alpha by intramuscular injection for 14 days, and then were treated 3 times per week for 24 weeks. RESULTS The extent of hepatic fibrosis, particularly, perisinusoidal fibrosis (P < 0.01) was significantly greater in nonresponders than in responders. The mean serum hyaluronate and type IV collagen levels were more elevated in nonresponders than in responders, especially, the serum hyaluronate level showed a significant difference (P < 0.01). Most of the patients having a serum hyaluronate level of more than 100 ng/ml were nonresponders who had chronic active hepatitis with bridging necrosis on liver biopsy. Serum hyaluronate and type IV collagen levels showed significant positive correlation with degree of the portal fibrosis (P < 0.01), perisinusoidal fibrosis (P < 0.001) and focal necrosis (P < 0.01) in histological findings of liver biopsy specimens. CONCLUSIONS These results suggest that serum hyaluronate and type IV collagen levels reflect the extent of the hepatic fibrosis in chronic hepatitis C and also that serum hyaluronate level predicts the response to interferon-alpha therapy in patients with chronic hepatitis C.