SUMMARY Although in common use, there is still controversy as to the way in which gold and penicillamine act in rheumatoid arthritis (RA).In this study, synovial fluids from 4 groups of patients have been compared: (1) RA patients on gold/penicillamine, (2) RA patients on non-steriodal anti-inflammatory drugs (NSAID) only, (3) osteoarthritis patients, and (4) patients with sero-negative arthropathies. The parameters measured were differential agglutination titre (DAT), total haemolytic complement (CH50), total protein, total white cell count, and immunoglobulins. RA patients on gold/penicillamine have lower synovial DAT levels and higher CH50 levels than RA patients on NSAID only, and total and cryoprecipitable IgM levels very close to those found in the sero-negative joint fluids. The non-specific inflammatory parameters, ie, white cell count and total protein are unchanged after gold/penicillamine therapy.In a second study, the serum DATs of patients in total remission after gold/penicillamine were compared with similar patients on NSAID only. The DAT falls significantly in the former group (P<0 *001), but not in the latter suggesting that fall in DAT is a consequence of therapy rather than remission.The parameters altered by gold/penicillamine in the synovial fluid are those that distinguish RA from non-rheumatoid arthropathies suggesting the drug's primary effect is to render the disease sero-negative. The results support the hypothesis that both drugs have a common mode of action based on their active thiol groups, and that the fall in DAT is due to the reduAtion of the antigenicity of the IgG complexes.