Rheumatoid arthritis (RA) patients develop a chronic inflammation in synovial joints and often in other tissues. Since efforts to isolate microbial agents from the involved sites have failed to confirm an infectious origin, it is generally agreed that RA is an autoimmune disease. However, the mechanisms initiating and maintaining the abnormal immune response remain poorly understood. The number ofNKT cells is reduced in several human autoimmune disorders and in animal models of autoimmunity. The purpose of this study was to investigate whether the frequency of CD161+ NKT cells in RA correlates with clinical disease parameters. As a group, RA patients had approximately three times less CD161+ CD4+ T cells in their PB than age and sex matched controls, as expected. In contrast, the number ofCD161+ CD4+ Tcells in the SF was 2.5-3 times higher than in the PB of the same patient. There was no obvious correlation between the frequency of these cells and clinical parameters. Despite reductions in absolute CD161+ cell numbers in RA PB, the abundance of the mRNA coding for this protein was higher in the patiept group than in controls. Furthermore, CD161 message expression showed a bimodal distribution. High CD161 abundance correlated with the lack of erosions, while low levels - with erosive changes. These observations held both in newly diagnosed patients (disease duration < 6 months) and the established RA group (disease duration> 3 years). This study confirms the loss of CD161+ CD4+ T lymphocytes in the PB ofRA patients. However, the frequency of these cells was comparatively higher in the SF. Significantly increased mRNA expression by PB CD161+ cells may indicate an activation-induced intemalisation of this receptor from the cell surface that, due to differences in the immunological microenvironment, does not happen in the SF. CD161 upregulation appear to be a disease-specific event in RA. Furthermore, the correlation between low CD161 expression levels and formation of erosions in RA may be used to predict longterm disease outcome in patient