The concentration of alpha 2-macroglobulin (alpha 2-M) in human gingival sulci has been investigated in two studies: first, in gingival washings during a 21-day period of experimental gingivitis in eight human volunteers and, second, in crevicular fluid collected with filter paper strips before and after initial periodontal therapy in 11 patients. The concentration of total alpha 2-M was found to increase in the washings of the volunteers throughout the period of experimental gingivitis. In the group of patients receiving periodontal therapy, the absolute amount of alpha 2-M in the fluid showed a significant decrease after therapy. The gingival index of inflammation and the crevicular fluid flow also decreased significantly. The specific content of the inhibitor (micrograms of alpha 2-M per mg of fluid per min), however, was found to increase in the fluid with decreasing inflammation. As detected by crossed immunoelectrophoresis, the fluid collected in these patients before therapy, in the presence of severe inflammation, invariably showed peaks of both free and complexed alpha 2-M. In contrast, the fluid collected from the same sites after healing of the inflammation contained no detectable free alpha 2-M.