The progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is one of the hallmarks of Parkinson's disease (PD). Neuroinflammation has been proposed to contributes to the progressive nature of the disease. Early growth response-1 (Egr-1), a zinc finger transcription factor, has been shown to have a crucial role in both neuronal death and the inflammatory response. However, whether and how Egr-1 is involved in the pathogenesis of PD has not been investigated. Using the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, we identified early peak induction of Egr-1 in the SNpc but not in the striatum. In situ immunofluorescent analysis showed that Egr-1 predominantly locates in the nuclei of nigral AldoC (+) astrocytes upon MPTP treatment. Genetic ablation of Egr-1 or inhibition of its transcriptional activity by Mithramycin A significantly suppresses the activation of both astrocytes and microglia, decreases proinflammatory cytokine expression, and protects dopaminergic cell bodies from degeneration in the SNpc. Taken together, these findings demonstrate that the induction of Egr-1 promotes neuroinflammation and dopaminergic cell body loss in the SNpc of MPTP-induced mouse model, suggesting an important role of astrocytic Egr-1 in neuroinflammation in PD.