Coincubation of neutrophils with TNF inhibited the chemoattractant-directed migration of neutrophils under agarose and enhanced their migration in the multiwell chemotaxis chamber. To assess the physiological significance of these differing in vitro TNF effects, ex vivo and in vivo investigations were performed using animal models. Neutrophils from the peripheral blood of rabbits preadministered systemic TNF showed impaired ability to migrate toward chemoattractants in vitro. In addition, systemic TNF administration suppressed zymosan-activated plasma-induced local accumulation of leukocytes in mouse skin. The results indicate that circulating TNF may act as a suppressor for local inflammatory reaction.