The use of two new assays was evaluated for predicting the response to interferon (IFN) therapy in patients with chronic hepatitis C. The genotype of hepatitis C virus (HCV) was establishe by an enzyme-linked immunosorbent assay based on genotype-specific recombinant peptides of the NS4 region (genotyping ELISA). The concentration of HCV RNA was measured by a branched DNA assay (bDNA assay). Seventy-eight patients received the same regimen of IFNα2a. Of the 74 patients assessed who completed the program, 38 (51.4%) were responders; i.e., their serum aminotransferase levels remained normal for 6 months or longer after stopping IFN, while 36 (48.6%) were nonresponders. The results of the HCV genotype determined by the genotyping ELISA and by the polymerase chain reaction (PCR) assay based on genotype specific primers were similar. The serum concentrations of HCV RNA as measured by the bDNA assay and by the competitive PCR assay correlated closely and significantly (r = 0.82, P< 0.0011. Multiple logistic regression analysis showed that the serum concentration of HCV RNA determined by the bDNA assay, the HCV genotype determined by the genotyping ELISA, and the histology activity index (HAI) of the liver were independently associated with IFN efficacy. By using these three variables in combination, a predictive rate of 82.4% was obtained. A lower level of HCV RNA, genotype 2 and a lower HAI score for liver histology were predictive of a favorable response to IFN. Thus, the genotyping ELISA and the bDNA assay appear to be useful for clinical management of patients receiving IFN therapy. © 1995 Wiiey-Liss, Inc.