In this study, we examined whether omega-3 (n-3) polyunsaturated fatty acids (PUFAs) may exert neuroprotective action in Parkinson's disease, as previously shown in Alzheimer's disease. We exposed mice to either a control or a high n-3 PUFA diet from 2 to 12 months of age and then treated them with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 140 mg/kg in 5 days). High n-3 PUFA dietary consumption completely prevented the MPTP-induced decrease of tyrosine hydroxylase (TH)-labeled nigral cells (P<0.01 vs. MPTP mice on control diet), Nurr1 mRNA (P<0.01 vs. MPTP mice on control diet), and dopamine transporter mRNA levels (P<0.05 vs. MPTP mice on control diet) in the substantia nigra. Although n-3 PUFA dietary treatment had no effect on striatal dopaminergic terminals, the high n-3 PUFA diet protected against the MPTP-induced decrease in dopamine (P<0.05 vs. MPTP mice on control diet) and its metabolite dihydroxyphenylacetic acid (P<0.05 vs. MPTP mice on control diet) in the striatum. Taken together, these data suggest that a high n-3 PUFA dietary intake exerts neuroprotective actions in an animal model of Parkinsonism.