The majority of rheumatoid arthritis (RA) synovial fluid lymphocytes (SFL) demonstrate markers that are suggestive of prior activation. While the mechanism(s) responsible is unknown, prior studies have suggested that certain Mycobacterium tuberculosis (MT) antigens may preferentially activate SFL in vitro. We therefore examined the ability of RA SFL to respond to purified protein derivative and an acetone-precipitable MT antigenic complex (AP-MT) and compared this with the responses by peripheral blood lymphocytes (PBL). The responses were contrasted with those elicited with tetanus toxoid (TT) and mitogenic anti-CD3. In patients with RA, the SF proliferative responses to both TT and anti-CD3 were reduced compared with responses by PB. In contrast, the SF response to purified protein derivative was maintained, and that to AP-MT was significantly increased, compared with PB. SF responses to AP-MT antigens were significantly greater than those to TT. The AP-MT activation of T lymphocytes from RA SF was characterized by an earlier peak proliferative response than that noted with matched PB. AP-MT responsiveness was not restricted to HLA-DR4 positive From the