The significance of immunoglobulin (Ig) M antibody to hepatitis C virus core protein (IgM anti-HCVcore) was studied in 41 patients with chronic hepatitis C virus (HCV) infection diagnosed by the polymerase chain reaction (PCR). IgM anti-HCVcore was tested with a solid-phase enzyme-linked immunoassay. The results were correlated with clinical features, liver histology findings evaluated by the histological activity index, and virological features such as genotypes and viremic levels assessed by a branched DNA assay. IgM anti-HCVcore was found in 29 (71%) patients, and its occurrence was only related to viremic levels. A significant relationship was observed between viremic levels and IgM anti-HCVcore cut-off index (rs = .42, P < .01). Of the eight low viremic (branched DNA-negative) patients, only two (25%) tested positive for IgM anti-HCVcore with a low cut-off index of <3, whereas 27 (82%) of the 33 highly viremic (branched DNA-positive) patients had IgM anti-HCVcore (P < .01). After a 28-week interferon-α course (IFN-α), sustained aminotransferase normalization after therapy withdrawal was achieved by only two (13%) of the 16 patients with IgM anti-HCVcore cut-off index >3 compared with 11 (44%) of the 25 patients with that <3 (P < .05). IgM anti-HCVcore cut-off index decreased after therapy in patients who cleared the virus in sera but increased again after reappearance of viremia. These findings suggest that IgM anti-HCVcore may serve as a simple serological indicator of active virus replication and have relevance to the outcome of antiviral therapy. (Hepatology 1995; 22:402–406.)