The presence, antigenic specificity, and clinical role of lymphocytotoxic antibodies (LCAs) were studied in 72 Israeli patients with rheumatoid arthritis (RA). Using the microlymphocytotoxicity assay on a cell panel of 47 donors, LCAs were found in 55% of the 72 RA sera, each displaying a distinct pattern of anti-lymphocytic reactivity, mostly against B lymphocytes. Human lymphocytic antigens (HLA) analysis of donors' lymphocytes suggested that activity of LCA-positive RA sera is HLA directed in 60% of cytotoxic sera. The anti-HLA antibodies found were not autoreactive and were not restricted to a particular class I or class II antigen. Relating the presence of LCAs to selective clinical features revealed that LCAs are inversely associated with the presence of an erosive disease (P <0.01) and with the patients' HLA-DQw1 (P <0.01). These findings suggest that LCAs in Israeli patients with RA are very common, multispecific and may have a protective role not mediated through interaction with self-HLA antigens.