Although increased production of prostaglandin E₂ (PGE₂) has been implicated in tissue damage in several pathological settings, the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE₂ synthesis, in dopaminergic neurodegeneration remains unclear. Here we show that mPGES-1 is up-regulated in the dopaminergic neurons of the substantia nigra of postmortem brain tissue from PD patients and in 6-hydroxydopamine (6-OHDA)-induced PD mice. The expression of mPGES-1 was also up-regulated in cultured dopaminergic neurons stimulated with 6-OHDA. The genetic deletion of mPGES-1 not only abolished 6-OHDA-induced PGE₂ production but also attenuated 6-OHDA-induced dopaminergic neurodegeneration both in vitro and in vivo, while it did not affect the productions of PGI₂, PGD₂ and TXA_2. Nigrostriatal projections, striatal dopamine content, and neurological functions were significantly impaired by 6-OHDA administration in wild-type mice, but not in mPGES-1 knockout mice. These results suggest that induction of mPGES-1 in dopaminergic neurons enhances 6-OHDA-induced dopaminergic neurodegeneration through excessive PGE₂ production. Thus, mPGES-1 may be a valuable therapeutic target for treatment of PD