Protein binding of sodium salicylate in synovial fluid and in serum from 23 inpatients with rheumatic diseases were studied, ex vivo, by equilibrium dialysis. Scatchard model with two classes of sites was used as a mathematical tool. At therapeutic concentrations, protein binding of sodium salicylate was significantly higher in serum than in synovial fluid. The ratio of areas under the curves for bound concentrations for synovial fluid to that for serum was 0.867. This difference was attributed to the hypoalbuminemia observed in the synovial fluid; for a given molar ratio of drug to albumin, or in other words, for the same amount of available drug per mole of albumin. The number of sites occupied was the same in the two biological media.