Our objective was to estimate the effect of interferon (IFN) on the evolution of fibrosis in chronic hepatitis C and the significance of the N-terminal propeptide of procollagen type III (PIIIP) as a marker of fibrogenesis. One hundred seventeen patients, 72 male (61%) and 45 female (39%), with a mean age of 40.7+/-11.9 years were treated with a2b-IFN, 3 to 5 MU, for 12 months: sustained responders (SR = 44), relapsers (RR = 35), and nonresponders (NR = 38). Liver biopsies were performed before treatment and 1 year after cessation of IFN for evaluation of the histological activity index (HAI). Serum PIIIP was obtained at the time of liver biopsy, at the beginning, during, and end of therapy and during the follow-up. The normal value in 29 healthy individuals was 0.37+/-0.18 U/L. Staging was reduced in 58% of SR, 12.5% of RR, and 11.5% of NR. There was a correlation between PIIIP and the HAI before (n = 71, r(s) = 0.41, P < 0.0004) and after IFN (n = 71, r(s) = 0.58, P < 0.0001). The SR had a better improvement in grading (90.3%; P < 0.05) and staging (58%; P < 0.001). The correlation of the HAI parameters with the variation of PIIIP showed significance only for fibrosis (r(s) = 0.36, P < 0.002) and portal inflammation (r(s) = 0.35, P < 0.01). PIIIP normalized only in patients whose fibrosis improved (P < 0.01). At the end of therapy, PIIIP had a predictive value in the distinction of SR from RR (PPV, 64; PNV, 55.6). During the follow-up, PIIIP remained lower in SR compared with RR and NR (P < 0.002). The response to a-IFN improved liver inflammation and fibrosis. Serum PIIIP is a useful noninvasive method to evaluate serially fibrogenesis in chronic hepatitis C treated with IFN.