The antiarthritic activity of a novel thiazole derivative, SM-8849, was compared with that of indomethacin and D-penicillamine, in mice with collagen-induced arthritis. SM-8849 reduced the incidence and severity of disease in collagen-immunized mice, as assessed by clinical observation. This efficacy was also confirmed by radiographic and histologic studies. Indomethacin produced an apparent reduction of the clinical score, but had only a marginal effect on bone destruction. D-penicillamine did not produce any improvement. Unlike indomethacin and D-penicillamine, SM-8849 reduced the serum levels of anti-type II collagen antibodies. Flow cytometric analysis of spleen cells from arthritic mice revealed an increase in T cells expressing activation antigens (class II antigens) in comparison with normal mice. Treatment with SM-8849, but not indomethacin or D-penicillamine, prevented the increase in Ia-bearing T cells. The results suggest that an effect of SM-8849 on immunocompetent cells may be responsible for the antiarthritic activity of the compound, and this would distinguish its action from that of traditional antirheumatic drugs.