Protein binding of salicylate in synovial fluid and plasma from patients with rheumatoid arthritis was studied by equilibrium dialysis. Protein binding in the synovial fluid was considerably lower at all salicylate concentrations studied (0.07 - 2.2 mM). Scatchard plots of the data were analyzed assuming binding to two classes of binding sites, each plasma sample being diluted to an albumin concentration equal to that in synovial fluid from the same patient. Binding to the primary binding sites was considerably decreased in synovial fluid in comparison with plasma. The affinity of the secondary binding sites was slightly lower. Thus, at a low therapeutic drug concentration, the decreased binding of salicylate to synovial fluid protein in patients with rheumatoid arthritis could mainly be accounted for by decreasing affinity of binding to the primary binding sites.