The value of rheumatoid factor (RF) isotypes for assessing rheumatoid arthritis (RA) remains debatable. We investigated whether using different antigens to measure RF alters the relationships between RF isotypes and clinical variables. The association between IgA and IgM RF, disease activity, and cumulative anatomical joint damage in RA was studied in 140 patients. The RF isotypes were measured using both rabbit IgG and horse IgG as antigens. Cumulative anatomical damage was assessed radiologically using Larsen's score and disease activity was determined by C-reactive protein (CRP), the health assessment questionnaire (HAQ), and a combined disease activity score (DAS). Patients positive for IgA RF and IgM RF against rabbit IgG had significantly higher disease activity and more radiological damage than negative patients. With horse IgG as antigen these differences were smaller or absent. Patients positive for only IgM RF had milder disease than patients positive for IgA RF with or without IgM RF. The clinical relationships of RF isotypes are related to the antigen used. Measuring IgA RF against rabbit IgG provides most information about disease activity, functional impairment and joint damage.