Background Chronic neuroinflammation is implicated in Parkinson's disease (PD). Inflammation involves the activation of microglia and astrocytes that release high levels of prostaglandins. There is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote PD neurodegeneration. The major prostaglandin in the mammalian brain is prostaglandin D2, which readily undergoes spontaneous dehydration to generate the bioactive cyclopentenone prostaglandins of the J2 series. These J2 prostaglandins are highly reactive and neurotoxic products of inflammation shown in cellular models to impair the ubiquitin/proteasome pathway and cause the accumulation of ubiquitinated proteins. PD is a disorder that exhibits accumulation of ubiquitinated proteins in neuronal inclusions (Lewy bodies). The role of J2 prostaglandins in promoting PD neurodegeneration has not been investigated under in vivo conditions. Methods We addressed the neurodegenerative and behavioral effects of the administration of prostaglandin J2 (PGJ2) simultaneously into the substantia nigra/striatum of adult male FVB mice by subchronic microinjections. One group received unilateral injections of DMSO (vehicle, n = 6) and three groups received PGJ2 [3.4 μg or 6.7 μg (n = 6 per group) or 16.7 μg (n = 5)] per injection. Immunohistochemical and behavioral analyses were applied to assess the effects of the subchronic PGJ2 microinfusions. Results Immunohistochemical analysis demonstrated a PGJ2 dose-dependent significant and selective loss of dopaminergic neurons in the substantia nigra while the GABAergic neurons were spared. PGJ2 also triggered formation of aggregates immunoreactive for ubiquitin and α-synuclein in the spared dopaminergic neurons. Moreover, PGJ2 infusion caused a massive microglia and astrocyte activation that could initiate a deleterious cascade leading to self-sustained progressive neurodegeneration. The PGJ2-treated mice also exhibited locomotor and posture impairment. Conclusion Our studies establish the first model of inflammation in which administration of an endogenous highly reactive product of inflammation, PGJ2, recapitulates key aspects of PD. Our novel PGJ2-induced PD model strongly supports the view that localized and chronic production of highly reactive and neurotoxic prostaglandins, such as PGJ2, in the CNS could be an integral component of inflammation triggered by insults evoked by physical, chemical or microbial stimuli and thus establishes a link between neuroinflammation and PD neurodegeneration.