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-α 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-α 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-α 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-α 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. The data presented indicate that serum IgM anti-HBc is a good surrogate marker for hepatocellular damage immunopathologically related to hepatitis B virus and is a better predictor of a beneficial response to interferon-α treatment than serum AST. IgM anti-HBc indicates the induction of the immune response to HBcAg during the course of chronic HBV infection but is not directly involved in the elimination of the infected hepatocytes. (Hepatology 1994;19:303–311).