The aim of this study was to evaluate the effect of interferon-alpha on liver fibrosis with an established quantitative histochemical method for determining collagen as a marker. 59 patients (31 men, 28 women; 47 +/- 14 yr) with chronic non-A, non-B hepatitis (92% with hepatitis C virus antibody) received subcutaneous injections of 3 or 1 MU recombinant interferon-alpha 2b or placebo thrice weekly for 24 wk. Needle-biopsy sections taken before and after interferon treatment were examined for histological evaluation and collagen quantitation. Values were compared with results obtained by means of morphometrical analysis of liver collagen and Knodell scoring histological index. The index of periportal and/or bridging necrosis was the only component of Knodell's histological score significantly decreased (p < 0.05) in patients treated with 3 MU interferon compared with placebo-treated controls. The fibrosis score was not significantly changed. In contrast, liver total collagen variations measured colorimetrically and morphometrically were significantly decreased in patients treated with 3 MU and 1 MU compared with the increase observed in the placebo-treated controls (p < 0.05). From these results, we conclude that a 6-mo course of 3 MU or 1 MU interferon-alpha 2b causes slight but nonetheless significant regression of liver fibrosis as assessed on the basis of quantitative estimation of liver collagen, irrespective of other response criteria, whereas progression of liver fibrosis can be observed in the absence of treatment.