Background: Antinuclear antibodies (ANA) giving a rim-like/membranous (RL/M) or a multiple nuclear dot (MN- D)pattern are highly specific for primary biliary cirrhosis (PBC).Aim and subj ects: To assess the prevalence of PBC specific ANAs, their Ig isotype, and their clinical significance in 90 PBC patients from Greece and Spain. Twenty eight pa tients with chronic hepatitis C, 23 patients with systemic lupus erythematosus,a nd 17 healthy subjects were studied as controls.Methods: PBC specific ANA reacti vity was tested by indirect immunofluorescence using HEp2 cells as substrate and individual Ig class (IgG, IgA, IgM) and IgG subclass (IgG1, IgG2,IgG3, IgG4) sp ecific antisera as revealing reagents. Results:Fourteen of 90 (15.6%) PBC patie nts had PBC specific ANA reactivity when an anti-IgG (total) antiserum was used as the revealing reagent while 58 (64.4%) were positive when specific antisera to each of the four IgG isotypes were used. The prevailing isotype was IgG3 for MND and IgG1 for RL/M. PBC patients with specific ANA, in particular of the IgG 3 isotype,had significantly more severe biochemical and histological disease com pared with those who were seronegative. None of the controls was positive. Concl usions: Disease specific ANA are present in the majority of patients with PBC wh en investigated at the level of immunoglobulin isotype. PBC specific ANA,in part icular of the IgG3 isotype, are associated with a more severe disease course, po ssibly reflecting the peculiar ability of this isotype to engage mediators of da mage. Background: Antinuclear antibodies (ANA) giving a rim-like / membranous (RL / M) or a multiple nuclear dot (MN- D) pattern are highly specific for primary biliary cirrhosis (PBC). Amim and subj ects: To assess the prevalence of PBC specific ANAs, their Ig isotype, and their clinical significance in 90 PBC patients from Greece and Spain. Twenty eight paients with chronic hepatitis C, 23 patients with systemic lupus erythematosus, a nd 17 healthy subjects were studied as controls. Methods: PBC specific ANA reacti vity was tested by indirect immunofluorescence using HEp2 cells as substrate and individual Ig class (IgG, IgA, IgM) and IgG subclass (IgGl, IgG2, IgG3, IgG4) Results: Fourteen of 90 (15.6%) PBC patients had PBC specific ANA reactivity when an anti-IgG (total) antiserum was used as the revealing reagent while 58 (64.4%) were positive when specific antisera to each of the four IgG isotypes were used. The prevailing isotype was IgG3 for MND and Ig G1 for RL / M. PBC patients with specific ANA, in particular of the IgG 3 isotype, had significantly more severe biochemical and histological disease com pared with those who were seronegative. None of the controls was positive. Concl usions: Disease specific ANA are present in the majority of patients with PBC wh en investigated at the level of immunoglobulin isotype. PBC specific ANA, in part icular of the IgG3 isotype, are associated with a more severe disease course, po ssibly reflecting the peculiar ability of this is to engage mediators of da mage.