In in vitro experiments, tumor necrosis factor (rHuTNFα) was found to inhibit spontaneous and directed migration of normal human neutrophils and monocytes. RHuTNFα showed no chemoattractant activity. In conjunction with a Phase‐2 clinical trial, we also studied in vivo rHuTNFα effects on neutrophil and monocyte number and function. At the time of maximal plasma TNF levels (30 min), marked neutropenia and monocytopenia were observed. Isolated neutrophils were activated for superoxide production but were unable to migrate. Monocyte migration was inhibited at later times. Neutrophil migratory function recovered between 4 and 8 h but was again depressed at 24 h. The data demonstrate the complexity of the response to TNF, comprising direct and indirect effects which are concentration‐, time‐ and place‐dependent. They further suggest that the only neutrophils and monocytes available for participation in an anti‐tumor activity of TNF in vivo are those present in the tumor at the outset.