Antihepatitis C virus (HCV) IgM antibodies were found in patients with both acute and chronic hepatitis C. The aims of the study were to determine the significance, in terms of liver disease and virological parameters, of anti-HCV core IgM antibodies in the serum of patients with chronic hepatitis C, and the possible relationship between the presence of these antibodies before treatment and biochemical and virological responses to interferon therapy. Sixty-one patients with chronic hepatitis C were studied. Tests for serum anti-HCV core IgM antibodies were carried out before treatment. The patients received 3 mega units of interferon alpha-2a subcutaneously thrice weekly for at least 3 months (6 months when alanine aminotransferase activity was normal at month 3). A biochemical response to interferon therapy was defined as normal alanine aminotransferase activity at the end of treatment (month 6: biochemical response) and 6 months later (month 12: sustained biochemical response). A sustained virological response was defined as serum HCV RNA negativity by a polymerase chain reaction-based detection method (PCR) in patients with normal alanine aminotransferase at month 12. Anti-HCV core IgM antibodies were detected in 28 of the 61 patients (46%). The prevalence of these antibodies was significantly higher in patients infected with HCV genotype 1 (including subtypes 1a and 1b) than in patients infected with other genotypes (including 2a and 3a) (57% vs. 17%; P < 0.01). No significant difference was found between IgM-positive and IgM-negative patients as regards the mean age, sex ratio, serum alanine aminotransferase and gamma-glutamyl transpeptidase activities, the prevalence of cirrhosis in liver biopsy specimens, detection of HCV RNA by PCR, and quantitation by branched DNA assay. At month 6 of interferon therapy, normal alanine aminotransferase activity was significantly more frequent in IgM-negative than in IgM-positive patients (52% vs. 21%, respectively; P < 0.02). At month 12, normal alanine aminotransferase activity and PCR negativity were significantly more frequent in IgM-negative than in IgM-positive patients (18% vs. 0%, P < 0.04). It is concluded that anti-HCV core IgM antibodies in serum are significantly more frequent in patients infected by HCV type 1 than by other types. This suggests that their overall prevalence in patients with chronic hepatitis C in industrialized countries, where HCV type 1 accounts for the majority of infections, would be of the order of 50%, that anti-HCV core IgM antibodies are not associated with characteristic features of liver disease, and that their presence before treatment is associated with a failure of interferon alpha therapy to clear the virus.