Serum IgM anti-HBc was determined in 135 chronic HBsAg carriers with various categories of histological activity on liver biopsy and hepatitis B serological profile. Thirty-three patients were treated with interferon-alpha to investigate the correlation between serum IgM anti-HBc with histological activity and viral replication, to evaluate the usefulness of pretreatment IgM anti-HBc as a predictor of a successful response to interferon-alpha and to examine the IgM anti-HBc response during this treatment. All 53 patients with chronic active hepatitis with either wild-type (n = 42) or precore mutant variant HBV infection (n = 11) had an IgM anti-HBc index greater than 0.300 compared with 7.4% (2 of 27) of the chronic HBsAg/HBeAg-positive carriers with chronic persistent hepatitis, 10% (3 of 30) of the anti-HBe-positive asymptomatic carriers and none of the 25 patients with hepatitis D virus-positive chronic active hepatitis (p < 0.0001). Pretreatment IgM anti-HBc index was greater than 0.300 in 82.4% (14 of 17) of HBeAg/HBV DNA-positive patients who seroconverted after interferon-alpha treatment compared with 25% (4 of 16) of the patients who did not seroconvert (p = 0.0013), whereas an elevated pretreatment AST was present in only 52.9% (9 of 17) of responders and in 37.5% (6 of 16) of nonresponders (p = 0.42). Serial testing of IgM anti-HBc in these 33 patients during interferon-alpha treatment showed a significant rise in IgM anti-HBc in all responders, which followed the AST flare-up but preceded the time of the HBeAg to anti-HBe seroconversion.(ABSTRACT TRUNCATED AT 250 WORDS)