Myelin removal in nerves undergoing wallerian degeneration mainly depends on invading, non-resident macrophages. The present study clarifies the role of serum complement components in this process in vitro and in vivo. Macrophages cocultured with degenerating nerves in vitro were unable to invade these nerves in the presence of C3-deficient serum. Application of C3-deficient serum subsequent to cellular invasion abolished the myelin phagocytic capacity of the invaded macrophages. This indicates that opsonization of myelin by complement components is necessary in myelin ingestion via macrophage receptors. In vivo, a monoclonal antibody to the macrophage complement receptor type 3 (CR3) significantly reduced myelin phagocytosis. Immunohistochemistry with anti-C3 antibodies showed a marked reaction in degenerating nerves. Immunoelectron microscopy localized C3 particles at the degenerating myelin sheaths. Haematogenous cells, invading the degenerating nerves, also showed a strong reaction for C3 in their cytoplasm. These results indicate that complement components play a critical role both in macrophage invasion of degenerating nerves and in the ingestion of myelin by these cells.