Molecular mimicry between mycobacterial antigens and components of human articular cartilage has been suggested to initiate the onset of rheumatoid arthritis (RA). Therefore, the proliferative response of peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MNC) towards a variety of mycobacterial antigen preparations was tested in patients with RA and various non-RA inflammatory joint diseases. The antigen panel included a recombinant 65 kDa heat shock protein of mycobacterial origin which has recently been shown to stimulate arthritogenic rat T cell clones. In our study, no significant response towards the 65 kDa protein was observed with PBMNC of patients with or without RA. When compared to normal donors, the reactivity towards heat killed BCG M. tuberculosis and purified protein derivative was reduced in the blood of patients with RA while enhanced in the non-RA group, however these differences did not reach statistical significance. The data obtained with PBMNC were in striking contrast to the proliferative response of SFMNC. In the majority of cases both with RA and non-RA joint diseases the latter compartment was far better stimulated by mycobacterial antigens including the 65 kDa protein compared to corresponding PBMNC. However, in some cases an enhanced stimulation of SFMNC was also obtained with tetanus toxoid. Our data suggest that the enhanced reactivity of SFMNC may be a common feature of several inflammatory joint diseases and is not restricted to RA. These findings may indicate a preferential homing of antigen reactive (memory) T cells to the inflamed joints while the circulating pool of lymphocytes is depleted of this population.