The neurotoxic drug p-chloramphetamine (PCA) causes widespread degeneration of fine, unmyelinated serotonergic (5-HT) axons in the forebrain. PCA toxicity is selective for 5-HT axon terminals; preterminal axons and cell bodies are spared. Degeneration is followed by slowly progressive axonal sprouting and partial reinnervation. PCA is injected subcutaneously; this route of administration avoids mechanical disruption of the blood brain barrier. The present study analyzed the response of microglia and astrocytes in rat brain to selective ablation of 5-HT axons by PCA. Several microglial markers were analyzed with immunocytochemical methods. An increase in the number of microglial processes and in immunoreactive staining was observed with antibodies directed against CR-3, MHC-I, CD4, and rat LCA. The microglial response was maximal 3 weeks after PCA treatment, became less evident 6 weeks after treatment, and by 9 weeks no difference was observed between treated and control rats. No change was detected in MHC-II or the macrophage marker ED1, nor in expression of GFAP by astrocytes. Thus, degeneration of 5-HT axon terminals affects only a subset of the microglial markers examined; in comparison, retrograde reaction to facial nerve transection causes a robust increase in all of these markers and in GFAP. The microglial response to PCA-induced axon loss is slow in onset and small in magnitude. These findings indicate that CNS microglia are activated by degeneration of fine, unmyelinated 5-HT axon terminals; furthermore, sensitive microglial markers can detect a subtle axonal lesion that provokes no detectable increase in GFAP expression by astrocytes.