Patients with rheumatoid arthritis (RA) have a reduced capacity for S-oxidation and formation of drug sulfate conjugates. We investigated S-methylation catalyzed by thiol methyl transferase (TMT) (E.C. 2.1.1.9) as an alternative pathway for metabolism of aliphatic compounds. TMT activity was measured in vitro using red blood cell membrane preparations from 120 patients with RA and 35 controls. Mean values for controls were 10.1 +/- 3 units/mg protein and for RA 3.7 +/- 3 units/mg protein (p less than 0.05). TMT activity was not related to the acute phase response or to drug administration. However, patients with RA with higher TMT activity tended to have higher rheumatoid factor levels. This evidence is consistent with a generalized disturbance of sulfur metabolism in rheumatoid disease.