In 27 patients with early Lyme disease, the mean response of peripheral blood mononuclear cells (PBMC) to Lyme spirochetal Borrelia burgdorferi antigens (723 counts per minute) was similar to that of control subjects. During convalescence, 2-3 weeks later, the patients' mean response was significantly higher (2,075 cpm, P less than 0.008). Compared with those with early disease, the PBMC of 22 patients with Lyme arthritis reacted even more to B burgdorferi (2,923 cpm, P less than 0.0004), and, by far, the greatest response was in concomitantly obtained synovial fluid mononuclear cells (15,238 cpm, P less than 0.001). The PBMC of patients with early Lyme disease reacted slightly less to phytohemagglutinin and pokeweed mitogen than those of normal control subjects, but patients with arthritis had greater than normal mitogen responses. In contrast, mitogen reactivity among synovial fluid cells was markedly decreased and correlated inversely with the response to antigen. Thus, in patients with Lyme disease, the antigen-specific responses of mononuclear cells increase as the disease progresses, and in those with arthritis, the greatest reactivity to antigen is found in cells in the inflamed joint.