Tumor necrosis factor (TNF) induces the production of two forms of soluble receptor (p55 and p75) that are present in human serum at concentrations that increase greatly in inflammatory rheumatic disease, as well as varying among healthy individuals. The purpose of this study was to evaluate the usefulness of soluble TNF receptors in distinguishing different forms of arthritis. Serum from patients with gout, rheumatoid arthritis, and osteoarthritis, and normal control subjects was analyzed for p55, p75, and TNF-alpha by enzyme-linked immunosorbent assay. Patients with gout had the highest level of soluble TNF receptor p55, while there was no significant difference in the level of this receptor between rheumatoid arthritis patients and controls. Both rheumatoid arthritis and gout patients had higher soluble TNF receptor p75 levels than osteoarthritis patients and control subjects, but there was no difference in the p75 level between rheumatoid arthritis and gout patients. Osteoarthritis patients had higher levels of p55 and lower levels of p75 than control subjects. The level of TNF-alpha in rheumatoid arthritis patients was higher than in osteoarthritis patients, gout patients, and control subjects. Determination of soluble TNF receptor levels, especially p55, might enable differentiation of rheumatoid arthritis from osteoarthritis and gout. The level of p75 cannot be utilized to differentiate rheumatoid arthritis and gout, in contrast to the results of previous investigations.