Mononuclear cells of the monocyte/macrophage system play an important role in myelin ingestion during Wallerian degeneration. The present in vitro study clarifies the role in this process of two macrophage-secreted cytokines, TNF-alpha and interleukin-1. Treatment with TNF-alpha massively reduced the amount of myelin ingested by macrophages via their complement receptor type 3 (CR3). Anti-TNF-alpha antibodies reversed the effect. Immunofluorescence of macrophages indicated that TNF-alpha caused a reduced expression of the CR3 by phagocytic cells. Further experiments revealed an interaction of TNF-alpha with its receptor on the macrophage cell membrane. Interleukin-1 had no effect on myelin ingestion in the in vitro system used in these experiments.