In recent retrospective studies, it was shown that subtypes of antimitochondrial antibodies (AMA) can help to discriminate between a benign [only anti-M9 and/or anti-M2 positive by enzyme-linked immunosorbent assay (ELISA)] and a rather progressive course (anti-M2, -M4 and/or -M8 positive). According to different constellations of these AMA subspecificities in ELISA and complement fixation test (CFT), four AMA profiles (A-D) were defined. In 1984 we started a prospective study based on 200 PBC patients with known AMA profiles in order to correlate the antibody pattern with the clinical outcome. Progression was defined primarily as the necessity of liver transplantation and death due to hepatic failure or variceal bleeding. At entry, 18 (9%) of the 200 patients had AMA profile A (only anti-M9), 57 (29%) profile B (only anti-M2 with or without anti-M9), 74 (37%) profile C (anti-M2 in association with anti-M4/-M8 by ELISA), and 51 (26%) profile D (anti-M2/-M4/-M8 by ELISA and CFT). At the beginning of the study, 177 patients had PBC stage I/II. During the observation period of ten years, ten patients died and in 18 orthotopic liver transplantation (OLT) was performed; all these patients belonged to profile C/D. Furthermore, 44% of the patients with profile C and 31% of the patients with profile D progressed to late stages, as defined by histology and clinical manifestations such as portal hypertension and increase of bilirubin, while only one of the patients with profile B and none of the profile A-patients developed late stage PBC. A significant increase of bilirubin was observed only in C/D-patients. AMA profiles did not change during the follow-up. In conclusion, AMA profiles discriminate between a benign and a progressive course of PBC already at early stages.