Wallerian degeneration in the CNS and PNS consists of degradation and phagocytosis of axons and their myelin sheath distal to the site of injury. This process of degeneration, which requires an effective macrophage response, occurs rapidly in peripheral nerves but is slow in the CNS. Rapid Wallerian degeneration in peripheral nerves may contribute to subsequent axonal regeneration. We show that there is a marked increase in mRNA expression of three pro-inflammatory molecules, the chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha), and the cytokine interleukin-1beta (IL-1beta), in the mouse sciatic nerve but not in the spinal cord undergoing Wallerian degeneration. Neutralizing MCP-1, MIP-1alpha and IL-1beta in the lesioned sciatic nerve with function-blocking antibodies suppressed macrophage responses and myelin clearance. Injecting recombinant MCP-1, MIP-1alpha or IL-1beta into the normal, uninjured spinal cord triggered the expression of a number of chemokines and cytokines. Furthermore, injecting recombinant MCP-1/MIP-1alpha or IL-1beta into the dorsal column of the spinal cord undergoing Wallerian degeneration triggered rapid macrophage/microglial activation and myelin clearance. These findings provide direct evidence that MCP-1, MIP-1alpha and IL-1beta are important regulators of macrophage responses that lead to rapid myelin breakdown and clearance in Wallerian degeneration.