In order to predict the complete response rate of natural interferon-alpha (nIFN-alpha) treatment in patients with chronic active hepatitis C, we examined the predictive value (PV) of different hepatitis C serological assays. We performed first generation (ver.1) and second generation (ver.2) hepatitis C virus (HCV) branched DNA-probe assays (bDNA-probe), HCV core protein assay (core protein), HCV Amplicor Monitor assay (amplicor monitor), and HCV competitive polymerase chain reaction (competitive PCR) assay, using serum samples collected immediately before initiation of treatment. For each marker, we studied, in patients stratified by serological group (Gr), which predictive value (PV) of the HCV titers showed association with the therapeutic effect. In 59 Gr 1 patients, complete response to nIFN-alpha treatment was predicted from the following PVs for each marker: 0.5 Meq/ml or less (odds ratio 11.7: P = 0.0010) with ver.1, 1.0 Meq/ml or less (odds ratio 5.3; P = 0.0119) with ver.2 of the bDNA-probe, 50 pg/ml or less (odds ratio 10.3; P = 0.0062) with core protein, 200 x 10(3) copy/ml or less (odds ratio 7.8; P = 0.0031) with amplicor monitor, and 10(4) copy/ml or less (odds ratio 6.2; p = 0.8395) with competitive PCR. In 27 Gr 2 patients, the PV for each marker indicating complete response was as follows: There was no relationship between PV and therapeutic effect with ver.1 of the bDNA-probe, while the PVs for the other markers were 0.2 Meq/ml or less (odds ratio 2.2; P = 0.3788) with ver.2, 20 pg/ml or less (odds ratio 5.6; P = 0.0597) with core protein, 400 x 10(3) copy/ml or less (odds ratio 4.0; P = 0.2965) with amplicor monitor, and 10(5.5) copy/ml or less (odds ratio 29.2; P = 0.0096) with competitive PCR. Our findings showed that complete response to the treatment may be predicted using the appropriate PV for each marker.