Although antihistone antibodies are frequently detected in patients with systemic lupus erythematosus, they appear to be uncommon or present only at low levels in rheumatoid arthritis (RA) patients. We used an enzyme-linked immunosorbent assay to study sera from 42 patients with RA, and we confirmed that antihistone antibodies mainly occurred at low levels in these patients. In contrast, 83% of 24 patients with Felty's syndrome had antihistone antibodies, often at high levels. Thus, antihistone antibodies may be a common autoimmune abnormality in patients with Felty's syndrome but not in other patients with RA. In addition, we demonstrated that some rheumatoid factors have cross-reactive antihistone antibody activity.